Tyk-2 inhibitor

ABSTRACT

Disclosed herein is a compound of Formula (I) for inhibiting TYK2 and treating a disease associated with the undesirable tyk-2 activity (tyk-2 related diseases), a method of using the compounds disclosed herein for treating inflammatory or autoimmune disease, and a pharmaceutical composition comprising the same.

FIELD OF THE DISCLOSURE

Disclosed herein is a compound of Formula (I) for inhibiting TYK2 and treating a disease associated with the undesirable tyk-2 activity (tyk-2 related diseases), a method of using the compounds disclosed herein for treating inflammatory or autoimmune diseases, and a pharmaceutical composition comprising the same.

BACKGROUND OF THE DISCLOSURE

Janus family of kinases includes JAK1, JAK2, JAK3, and tyrosine kinase 2 (Tyk2) and are nonreceptor tyrosine kinases that bind to the intracellular portion of cell surface cytokine receptors. In response to the stimulation of these receptors, the Janus kinases phosphorylate signal transducer and activator of transcription (STAT) proteins, which then dimerize, translocate to the nucleus, and activate gene transcription. Tyrosine kinase 2 (Tyk2) is a member of the Janus kinase (JAK) family of nonreceptor tyrosine kinases and has been shown to be critical in regulating the signal transduction cascade downstream of receptors for IL-12, IL-23 and type I interferons in both mice (Ishizaki, M. et al., “Involvement of Tyrosine Kinase-2 in Both the IL-12/TH1 and IL-23/TH17 Axes in vivo”, J. Immunol., 187: 181-189 (2011); Prchal-Murphyl, M. et al., “TYK2 kinase activity is required for functional type I interferon responses in vivo”, PloS one, 7:e39141 (2012)) and humans (Minegishi, Y. et al., “Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate acquired immunity”, Immunity, 25:745-755 (2006)). Tyk2 mediates the receptor-induced phosphorylation of members of the STAT family of transcription factors, an essential signal that leads to the dimerization of STAT proteins and the transcription of STAT-dependent pro-inflammatory genes. Tyk2-deficient mice are resistant to experimental model of colitis, psoriasis and multiple sclerosis, demonstrating the importance of Tyk2-mediated signaling in autoimmunity and related disorders (Ishizaki, M. et al., “Involvement of Tyrosine Kinase-2 in Both the IL-12/TH1 and IL-23/TH17 Axes in vivo”, J. Immunol., 187: 181-189 (2011); Oyamada, A. et al., “Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis”, J. Immunol., 2009, 183, 7539-7546).

To date, most of the known small molecule JAK inhibitors that have progressed into development are active site-directed inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain (also referred to as the JH1 or “Janus Homology 1” domain) of the JAK protein, which prevents catalytic activity of the kinase by blocking ATP, downstream phosphorylation, and resulting pathway signal transduction (Bryan, M. et al., “Kinase Inhibitors for the Treatment of Immunological Disorders: Recent Advances”, J Med. Chem. 2018, 61, 9030-9058). It's well-known that JAK2 is involved in hematopoiesis (Neubauer, H.; et al., “JAK2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis”, Cell 1998, 93, 397-409) and the inhibition of JAK2 can cause side effects such as anemia, neutropenia, and increased infection risk and dyslipidemia (Wollenhaupt, J., et al., “Safety and efficacy of tofacitinib, an oral Janus Kinase Inhibitor, for the treatment of rheumatoid arthritis in open-label. J. Rheumatol. 2014, 41, 837-852; He, Y., et al., Efficacy and safety of tofacitinib in the treatment of rheumatoid arthritis: a systematic review and meta-analysis. BMC Musculoskelet. Disord. 2013, 14, 298; Zerbini, C. A, et al., Tofacitinib for the treatment of rheumatoid arthritis. Expert Rev Clin. Immunol. 2012, 8, 319-331).

Small molecule inhibitors of TYK2-JH2 domain are being developed for treating autoimmune diseases. BMS986165 (WO2014074661A1, WO2018183649A1, WO2018183656A1 and WO2019232138A1) is a first-in-class of TYK2-JH2 inhibitor, currently undergoing multiple clinical trials in psoriasis, ulcerative colitis (UC), lupus and systemic lupus erythematosus. The other TYK2-JH2 inhibitor which entered clinical trials is ABBV-712 (See, for example, WO2019178079A1, WO2019178079A9, JP6557436B1, and US2019276450A1) and it is in a clinical trial for psoriasis.

SUMMARY OF THE DISCLOSURE

Disclosed herein provides a serial of compounds which inhibit the pseudokinase (JH2) domain of TYK2. These compounds showed picomolar to nanomolar biochemical activity in TYK2-JH2 binding assay and also showed nanomolar activity in cellular assay. In the meanwhile, these compounds showed excellent selectivity against JAK1 in biochemical assay and excellent selectivity against JAK2 in cellular assay.

In the present discourse, compounds bind to the pseudokinase (JH2) domain of TYK2 and inhibit its function through an allosteric mechanism. In the meanwhile, these compounds have greatly improved selectivity over other JAK family members (JAK1, JAK2 and JAK3).

In the first aspect, disclosed herein a compound of Formula (I)

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

X is N or CH;

Y is N, NR³ or CR³; L¹ is a direct bond, —(CR^(a)R^(b))—, —O—, —S—, —S(O)—, —SO₂—, —C(O)—, C(O)O—, —OC(O)—, —NR^(a)—, —O—(CR^(a)R^(b))_(q), —S—(CR^(a)R^(b))_(q)—, —S(O)—(CR^(a)R^(b))_(q)—, —SO₂—(CR^(a)R^(b))_(q)—, —C(O)—(CR^(a)R^(b))_(q)—, C(O)O—(CR^(a)R^(b))_(q)—, —OC(O)—(CR^(a)R^(b))_(q)—, —NR^(a)—(CR^(a)R^(b))₆—, —C(O)NR^(a)—, —NR^(a)C(O)—, —NR^(a)C(O)O—, —NR^(a)C(O)NR^(b)—, —SO₂NR^(a)—, —NR^(a)SO₂—, —NR^(a)S(O)₂NR^(b)—, —NR^(a)S(O)NR^(b)—, —C(O)NR^(a)SO₂—, —C(O)NR^(a)SO—, or —C(═NR^(a))NR^(b)—, wherein q is a number of 1 to 7, and, R^(a) and R^(b) are independently hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R¹ is —C₁₋₆alkyl, -haloC₁₋₆alkyl, —C₁₋₆ alkoxy, -haloC₁₋₆ alkoxyl, —C₃₋₆ cycloalkyl, aryl, or —NR^(c)R^(d); each of R², R³, and R⁴ is independently hydrogen, cyano, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —NO₂, —OR^(e), —SO₂R^(e), —COR^(e), —CO₂R^(e), —CONR^(e)R^(f), —C(═NR^(e))NR^(f)R^(g), —NR^(e)R^(f), —NR^(e)COR^(f), —NR^(e)CONR^(f)R^(g), —NR^(e)CO₂R^(f), —NR^(e)SONR^(f)R^(g), —NR^(e)SO₂NR^(f)R^(g), or —NR^(e)SO₂R^(f), wherein each of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently and optionally substituted with at least one substituent selected from i) cyano, -oxo-, halogen, —NR^(m)R^(n), —OR^(h), —C(O)NR^(m)R^(n); ii) heterocyclyl optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), substituted or unsubstituted —C₁₋₆alkyl, substituted or unsubstituted —C₁₋₆alkoxy or —C(O)NR^(m)R^(n); or, iii) C₁₋₆alkyl optionally substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂ or C₁₋₆alkoxy; wherein R^(h) is hydrogen, hydroxy, —NH₂, —C₁₋₆alkyl, C₁₋₆alkyl substituted with hydroxy, or heterocyclyl, R^(e), R^(f), and R^(g) are each independently hydrogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with one to three substituents selected from cyano, -oxo-, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₃₋₆cycloalkyl optionally substituted with halogen, hydroxy or —C₁₋₆alkoxy, —C(O)NR^(m)R^(n), or heterocyclyl; R⁵ is hydrogen or C₁₋₆alkyl; Cy¹ is 6- to 12-membered aryl or 5- to 14-membered heteroaryl, or 5- to 14-membered heterocyclyl, each of which is optionally substituted with at least one substituent R^(i), R^(i) is independently halogen, cyano, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, cyano (—CN), —NO₂, —OR^(j), —SO₂R^(j), —COR^(j), —CO₂R^(k), —CONR^(j)R^(k), —C(═NR^(j))NR^(k)R^(l), —NR^(j)R^(k), —NR^(j)COR^(k), —NR^(j)CONR^(k)R^(l), —NR^(j)CO₂R^(k), —NR^(j)SONR^(k)R^(l), —NR^(j)SO₂NR^(k)R^(l), or —NR^(j)SO₂R^(k), wherein each of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, —OR^(m), —C(O)R^(m), —NR^(m)R^(n), —C₁₋₆alkyl, C₁₋₆alkoxy-, C₁₋₆alkyl substituted with —C₁₋₆alkoxy or -oxo-; R^(j), R^(k), R^(l), R^(m), R^(n) are each independently hydrogen, —C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl-, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or (R¹ and R²), or (R² and R³), or (R³ and R⁴), together with the atoms to which they are attached, form a fused ring system, said fused ring system comprises 0-4 heteroatoms selected from oxygen (O), nitrogen (N) or sulfur (S) as ring member(s) and is optionally and independently substituted with halogen, —C₁₋₆ alkyl, —C₁₋₆alkoxy, C₁₋₆alkyl substituted with halogen, C₁₋₆alkoxy substituted with halogen or —C₃₋₆cycloalkyl; any of the said alkyl or alkoxy is optionally enriched in deuterium.

In some embodiments, disclosed herein is a compound of Formula (I-A)

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

X is N or CH;

L¹ is a direct bond, —(CR^(a)R^(b))_(q)—, —O—, —S—, —S(O)—, —SO₂—, —C(O)—, C(O)O—, —OC(O)—, —NR^(a)—, —O—(CR^(a)R^(b))_(q)—, —S—(CR^(a)R^(b))_(q)—, —S(O)—(CR^(a)R^(b))_(q)—, —SO₂—(CR^(a)R^(b))_(q)—, —C(O)—(CR^(a)R^(b))_(q)—, C(O)O—(CR^(a)R^(b))_(q)—, —OC(O)—(CR^(a)R^(b))_(q)—, —NR^(a)—(CR^(a)R^(b))_(q)—, —C(O)NR^(a)—, —NR^(a)C(O)—, —NR^(a)C(O)O—, —NR^(a)C(O)NR^(b)—, —SO₂NR^(a)—, —NR^(a)SO₂—, —NR^(a)S(O)₂NR^(b)—, —NR^(a)S(O)NR^(b)—, —C(O)NR^(a)SO₂—, —C(O)NR^(a)SO—, or —C(═NR^(a))NR^(b)—, wherein q is a number of 1 to 7, and, R^(a) and R^(b) are independently hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R¹ is —C₁₋₆alkyl, -haloC₁₋₆alkyl, —C₁₋₆alkoxy, -haloC₁₋₆alkoxyl, —C₃ cycloalkyl, aryl, or —NR^(m)R^(n); each of R², R³, and R⁴ is independently hydrogen, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl, -oxo-, —CN, —NO₂, —OR^(e), —SO₂R^(e), —COR^(e), —CO₂R^(e), —CONR^(e)R^(f), —C(═NR^(e))NR^(f)R^(g), —NR^(e)R^(f), —NR^(e)COR^(f), —NR^(e)CONR^(f)R^(g), —NR^(e)CO₂R^(f), —NR^(e)SONR^(f)R^(g), —NR^(e)SO₂NR^(f)R^(g), or —NR^(e)SO₂R^(f), wherein each of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently and optionally substituted with at least one substituents selected from cyano, oxo, halogen, C₁₋₆alkyl optionally substituted with halogen, C₁₋₆alkyl substituted with hydroxy (preferably, hydroxymethyl, hydroxyethyl), —OR^(h), —C(O)NR^(m)R^(n), —NH₂, —C₁₋₆alkyl substituted with —NH₂ or —C₁₋₆alkyl substituted with —C₁₋₆alkoxy-; wherein R^(h) is hydrogen, alkyl, hydroxy-C₁₋₆alkyl or heterocyclyl, R^(e), R^(f), and R^(g) are each independently hydrogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with one to three substituents selected from halogen, hydroxy, cyano, or —C₁₋₆alkoxy; —C₃₋₆cycloalkyl optionally substituted with halogen, hydroxy, or C₁₋₆alkoxy, or heterocyclyl; R⁵ is hydrogen or C₁₋₆alkyl; Cy¹ is 6- to 12-membered aryl or 5- to 14-membered heteroaryl, or 5- to 14-membered heterocyclyl, each of which is optionally substituted with at least one substituent R^(i), R^(i) is independently halogen, cyano, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO₂, —OR^(j), —SO₂R^(j), —COR^(j), —CO₂R^(k), —CONR^(j)R^(k), —C(═NR^(j))NR^(k)R^(l), —NR^(j)R^(k), —NR^(j)COR^(k), —NR^(j)CONR^(k)R^(l), —NR^(j)CO₂R^(k), —NR^(j)SONR^(k)R^(l), —NR^(j)SO₂NR^(k)R^(l), or —NR^(j)SO₂R^(k), wherein each of said —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, OR^(m), C(O)R^(m), —NR^(m)R^(n), —C₁₋₆alkyl, C₁₋₆alkoxy-, C₁₋₆alkoxy-C₁₋₆ alkyl-, or oxo; R^(j), R^(k), R^(l), R^(m), R^(n) are each independently hydrogen, —C₁₋₆alkyl, —C₁₋₆alkyl substituted with C₁₋₆alkoxy, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or (R¹ and R²), or (R² and R³), or (R³ and R⁴), together with the atoms to which they are attached, form a fused ring system, said fused ring system comprises 0-4 heteroatoms selected from oxygen, nitrogen or sulfur as ring member(s) and is optionally and independently substituted with halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, -haloC₁₋₆alkyl, -haloC₁₋₆alkoxy, or —C₃₋₆cycloalkyl; any of the said alkyl or alkoxy is optionally enriched in deuterium.

In some embodiments, X is N and Y is CR³. In some embodiments, X is N and Y is N. In some embodiments, X is CH and Y is N.

In some embodiments, R¹ is —C₁₋₃ alkyl, —NR^(c)R^(d) or —C₃₋₆ cycloalkyl, preferably —NH₂, methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclopentyl.

In some embodiments, R² and R⁴ are each independently hydrogen, halogen, —C₁₋₆alkyl, or —C₁₋₆alkoxy, preferably hydrogen, fluoro, methyl, methoxy, ethoxy, or isopropoxy.

In some embodiments, R³ is

-   -   hydrogen;     -   cyano;     -   halogen;     -   —C₁₋₄ alkyl optionally substituted with at least one substituent         independently selected from halogen, 3- to 6-membered         heterocyclyl or —OR^(h), wherein         3- to 6-membered heterocyclyl comprises one or two heteroatoms         selected from oxygen (O), nitrogen (N) or sulfur (O) as ring         member(s), optionally substituted with at least one substituent         independently selected from cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n),         wherein —C₁₋₆alkyl or —C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy; and         R^(h) is hydrogen, alkyl, or heterocyclyl;     -   —C₃₋₆cycloalkyl, optionally substituted with at least one         substituent independently selected from cyano, -oxo, halogen,         —NR^(m)R^(n), hydroxy, —C₁₋₆alkyl, —C₁₋₆alkoxy or         —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or C₁₋₆alkoxy is         substituted with at least one substitution independently         selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or         C₁₋₆alkoxy;     -   heterocyclyl comprising one or two heteroatoms selected from         oxygen (O), nitrogen (N) or sulfur (S) as ring member(s),         optionally substituted with at least one substituent         independently selected from cyano, -oxo-, halogen, hydroxy,         C₁₋₆alkyl, alkoxy, —NRR^(m)R^(n), or —C(O)NR^(m)R^(n), and         wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy;     -   —OR^(e), wherein R^(e) is —C₁₋₆alkyl, —C₃₋₆cycloalkyl, 3- to         6-membered heterocyclyl, or aryl, wherein         i) —C₁₋₆alkyl is optionally substituted with cyano, -oxo-,         halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkoxy-, —C₃₋₆cycloalkyl         optionally substituted with cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), —C₁₋₆alkyl, C₁₋₆alkoxy or —C(O)NR^(m)R^(n), 4- to         6-membered heterocyclyl optionally substituted with cyano,         halogen, hydroxy, C₁₋₆alkyl or C₁₋₆alkoxy; and,         ii) —C₃₋₆cycloalkyl or 3- to 6-membered heterocyclyl is         optionally substituted with cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), C₁₋₆alkyl, C₁₋₆alkoxy or —C(O)NR^(m)R^(n), wherein         —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one         substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆ alkyl or C₁₋₆alkoxy;     -   —C₅₋₁₀aryl; or     -   heteroaryl comprising one oxygen (O), nitrogen (N) or sulfur (S)         heteroatom as ring member, optionally substituted with at least         one substitution independently selected from cyano, -oxo,         halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or         —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or C₁₋₆alkoxy is         substituted with at least one substitution independently         selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or         C₁₋₆alkoxy;         and wherein R^(m) and R^(n) are independently selected from         hydrogen or C₁₋₃alkyl;         any of the said alkyl or alkoxy is optionally enriched in         deuterium.

In some embodiments, R³ is

-   -   hydrogen;     -   cyano;     -   halogen;     -   —C₁₋₄ alkyl optionally substituted with at least one substituent         independently selected from halogen, 3- to 6-membered         heterocyclyl or —OR, wherein         said 3- to 6-membered heterocyclyl comprises one or two         heteroatoms selected from oxygen (O), nitrogen (N) or sulfur (O)         as ring member(s), optionally substituted with at least one         substituent independently selected from cyano, -oxo, halogen,         hydroxy, —NR^(m)R^(n), C₁₋₆alkyl, —C₁₋₆alkoxy or         —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or C₁₋₆alkoxy is         substituted with at least one substitution independently         selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or         C₁₋₆alkoxy, and,         R^(h) is hydrogen, alkyl or heterocyclyl (preferably 3- to         6-membered heterocyclyl, e.g., tetrahydrofuranyl,         thiazolidinyl);     -   —C₃₋₆cycloalkyl, optionally substituted with at least one         substituent independently selected from cyano, -oxo, halogen,         —NR^(m)R^(n), hydroxy, —C₁₋₆alkyl, —C₁₋₆alkoxy or         —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or C₁₋₆ alkoxy is         substituted with at least one substitution independently         selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or         C₁₋₆alkoxy;     -   heterocyclyl, preferably 4- to 6-membered monocyclic saturated         heterocyclyl, saturated mono-spiro heterocyclyl, saturated         bicyclic fused heterocyclyl, or saturated bridged heterocyclyl,         comprising one or two heteroatoms selected from oxygen (O),         nitrogen (N) or sulfur (S) as ring member(s), more preferably         morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl,         1,4-dioxanyl, piperidinyl or azetidinyl, optionally substituted         with at least one substituent independently selected from cyano,         -oxo, halogen, hydroxy, —C₁₋₆alkyl, alkoxy, —NR^(m)R^(n), or         —C(O)NR^(m)R^(n), and wherein —C₁₋₆alkyl or —C₁₋₆-alkoxy is         substituted with at least one substitution independently         selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆ alkyl or         C₁₋₆alkoxy;     -   —OR^(e), wherein R^(e) is —C₁₋₆alkyl, —C₃₋₆cycloalkyl, 3- to         6-membered heterocyclyl (preferably 4- to 6-membered monocyclic         saturated heterocyclyl comprising one oxygen heteroatom as ring         member), or aryl, wherein         i) —C₁₋₆alkyl is optionally substituted with cyano, -oxo-,         halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkoxy-, —C₃₋₆cycloalkyl         optionally substituted with cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), —C₁₋₆alkyl, C₁₋₆alkoxy or —C(O)NR^(m)R^(n), 4- to         6-membered heterocyclyl optionally substituted with cyano,         halogen, hydroxy, —C₁₋₆ alkyl or —C₁₋₆alkoxy; and,         ii) —C₃₋₆cycloalkyl or 3- to 6-membered heterocyclyl is         optionally substituted with cyano, -oxo, halogen, hydroxy,         NR^(m)R^(n), C₁₋₆alkyl, C₁₋₆alkoxy or —C(O)NR^(m)R^(n), wherein         —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one         substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆ alkyl or C₁₋₆alkoxy;     -   —C₅₋₁₀aryl; or     -   heteroaryl, preferably 5- to 6-membered heteroaryl comprising         one oxygen (O), nitrogen (N) or sulfur (S) heteroatom as ring         member, optionally substituted with at least one substitution         independently selected from cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n),         wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy;         and wherein R^(m) and R^(n) are independently selected from         hydrogen or C₁₋₃alkyl.

In some embodiments, R³ is

-   -   hydrogen, cyano, halogen;     -   —C₁₋₄ alkyl optionally substituted with at least one substituent         independently selected from halogen, 3- to 6-membered         heterocyclyl or —OR^(h), wherein         Said 3- to 6-membered heterocyclyl is selected from morpholinyl,         tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl,         1,4-dioxanyl, piperidinyl, thiazolidinyl or azetidinyl, each of         which is optionally substituted with at least one substituent         independently selected from cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), C₁₋₆ alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n),         wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy, and, R^(h) is hydrogen,         C₁₋₆alkyl or 3- to 6-membered heterocyclyl (e.g.,         tetrahydrofuranyl or thiazolidinyl);     -   —C₃₋₆cycloalkyl, optionally substituted with at least one         substituent independently selected from cyano, -oxo, halogen,         NR^(m)R^(n), hydroxy, —C₁₋₆alkyl, —C₁₋₆alkoxy or         —C(O)NR^(m)R^(n), hydroxy, or C₁₋₆alkoxy, wherein —C₁₋₆alkyl or         C₁₋₆alkoxy is substituted with at least one substitution         independently selected from cyano, halogen, hydroxy, —NH₂,         —C₁₋₆alkyl or C₁₋₆alkoxy;     -   heterocyclyl is selected from morpholinyl, tetrahydrofuranyl,         tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl or         azetidinyl, optionally substituted with at least one substituent         independently selected from cyano, -oxo, halogen, hydroxy,         C₁₋₆alkyl, alkoxy, —NRR^(m)R^(n), or —C(O)NR^(m)R^(n), and         wherein —C₁₋₆alkyl or —C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or —C₁₋₆alkoxy;     -   —OR^(e), wherein R^(e) is —C₁₋₆alkyl, —C₃₋₆cycloalkyl, 4- to         6-membered monocyclic saturated heterocyclyl comprising one         oxygen heteroatom as ring member, or C₆₋₁₀aryl, wherein         i) —C₁₋₆alkyl is optionally substituted with cyano, -oxo-,         halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkoxy-, —C₃₋₆cycloalkyl         optionally substituted with cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n), 4- to         6-membered heterocyclyl optionally substituted with cyano,         halogen, hydroxy, —C₁₋₆ alkyl or —C₁₋₆alkoxy; and,         ii) —C₃₋₆cycloalkyl or 3- to 6-membered heterocyclyl is         optionally substituted with cyano, -oxo, halogen, hydroxy,         NR^(m)R^(n), C₁₋₆alkyl, C₁₋₆alkoxy or —C(O)NR^(m)R^(n), wherein         —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one         substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy;     -   —C₆₋₁₀aryl; or     -   5- to 6-membered heteroaryl selected from pyridinyl,         pyridazinyl, pyrazinyl, thiazolyl or isoxazolyl, each of which         is optionally substituted with at least one substitution         independently selected from cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n),         wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy;         and wherein R^(m) and R^(n) are independently selected from         hydrogen or —C₁₋₃alkyl.

In some embodiments, R³ is

-   -   hydrogen, cyano, halogen;     -   —C₁₋₄ alkyl optionally substituted with at least one substituent         independently selected from halogen, hydroxy, C₁₋₃alkoxy,         thiazolidin-3-yl optionally substituted with at least one         substituent independently selected from cyano, -oxo, halogen,         hydroxy, —NR^(m)R^(n), or —C₁₋₃alkyl;     -   —C₃₋₆cycloalkyl, optionally substituted with at least one         substituent independently selected from cyano, -oxo, halogen,         —NR^(m)R^(n), hydroxy, —C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein         —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one         substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or —C₁₋₃alkoxy;     -   heterocyclyl is selected from morpholinyl, tetrahydrofuranyl,         tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl or         azetidinyl, optionally substituted with at least one substituent         independently selected from cyano, -oxo, halogen, hydroxy,         C₁₋₆alkyl, alkoxy, —NR^(m)R^(n), or —C(O)NR^(m)R^(n), and         wherein —C₁₋₆ alkyl or C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or —C₁₋₆alkoxy;     -   —OR^(e), wherein R^(e) is —C₁₋₆alkyl, —C₃₋₆cycloalkyl, 4- to         6-membered monocyclic saturated heterocyclyl comprising one         oxygen heteroatom as ring member, or C₆₋₁₀aryl, wherein         i) —C₁₋₆alkyl is optionally substituted with cyano, -oxo-,         halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkoxy-, —C₃₋₆cycloalkyl         optionally substituted with cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n), 4- to         6-membered heterocyclyl optionally substituted with cyano,         halogen, hydroxy, —C₁₋₆ alkyl or —C₁₋₆alkoxy; and,         ii) —C₃₋₆cycloalkyl or 3- to 6-membered heterocyclyl is         optionally substituted with cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n),         wherein —C₁₋₆alkyl or —C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or —C₁₋₆alkoxy;     -   —C₆₋₁₀aryl; or     -   5- to 6-membered heteroaryl selected from pyridinyl,         pyridazinyl, pyrazinyl, thiazolyl or isoxazolyl, each of which         is optionally substituted with at least one substitution         independently selected from cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n),         wherein —C₁₋₆alkyl or —C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or —C₁₋₆alkoxy;         and wherein R^(m) and R^(n) are independently selected from         hydrogen or —C₁₋₃alkyl.

In some embodiments, R³ is

-   -   hydrogen, cyano, halogen;     -   methyl, ethyl, propyl or butyl, each of which optionally         substituted with at least one substituent independently selected         from halogen, hydroxy, methoxy, ethoxy, propoxy, or         2,4-dioxothiazolidin-3-yl;     -   cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of         which is optionally substituted with at least one substituent         independently selected from cyano, -oxo, halogen, —NR^(m)R^(n),         hydroxy, —C₁₋₃alkyl, or —C₁₋₃alkoxy, wherein —C₁₋₃alkyl or         C₁₋₃alkoxy is optionally substituted with at least one         substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₃alkyl or —C₁₋₃alkoxy;     -   heterocyclyl is selected from morpholin-2-yl, morpholin-3-yl,         morpholin-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,         tetrahydropyran-2-yl, tetrahydropyran-3-yl,         tetrahydropyran-4-yl, pyrrolidine-1-yl, pyrrolidin-2-yl,         pyrrolidin-3-yl, 1,4-dioxan-2-yl, piperidin-1-yl,         piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, azetidin-1-yl,         azetidine-2-yl, azetidin-3-yl, 5-azaspiro[2.4]heptanyl,         3-azabicyclo[3.1.0]hexan-3-yl or 2-azabicyclo[3.1.0]hexan-2-yl,         each of which is optionally substituted with at least one         substituent independently selected from cyano, -oxo, halogen,         hydroxy, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NR^(m)R^(n), or         —C(O)NR^(m)R^(n), and wherein —C₁₋₆alkyl or C₁₋₆alkoxy is         substituted with at least one substitution independently         selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or         —C₁₋₆alkoxy;     -   —OR^(e), wherein R^(e) is         i) methyl, ethyl, propyl (iso-propyl), butyl, pentyl or hexyl,         each of which is optionally substituted with deuterium, cyano,         -oxo-, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₃alkoxy-,         —C₃₋₆cycloalkyl optionally substituted with cyano, -oxo,         halogen, hydroxy, —NR^(m)R^(n), —C₁₋₃alkyl, —C₁₋₃alkoxy or         —C(O)NR^(m)R^(n), or 4- to 6-membered heterocyclyl optionally         substituted with cyano, halogen, hydroxy, —C₁₋₃alkyl or         —C₁₋₃alkoxy; or,         ii) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,         morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,         tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,         tetrahydropyran-2-yl, tetrahydropyran-3-yl,         tetrahydropyran-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,         pyrrolidin-3-yl, 1,4-dioxan-2-yl, piperidin-1-yl,         piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, azetidin-1-yl,         azetidine-2-yl or azetidin-3-yl, each of which is optionally         substituted with cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n),         —C₁₋₃alkyl, —C₁₋₃alkoxy or —C(O)NR^(m)R^(n), wherein —C₁₋₃alkyl         or —C₁₋₃alkoxy is substituted with at least one substitution         independently selected from cyano, halogen, hydroxy, —NH₂,         —C₁₋₃alkyl or —C₁₋₃alkoxy;     -   —C₆₋₁₀aryl; or     -   5- to 6-membered heteroaryl selected from pyridin-1-yl,         pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-1-yl,         pyridazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-1-yl,         pyrazin-2-yl, thiazol-2-yl, thiazol-3-yl, thiazol-4-yl,         isoxazol-2-yl, isoxazol-3-yl or isoxazol-4-yl, each of which is         optionally substituted with at least one substitution         independently selected from cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), —C₁₋₃alkyl, —C₁₋₃alkoxy or —C(O)NR^(m)R^(n),         wherein —C₁₋₃alkyl or —C₁₋₃alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₃alkyl or C₁₋₃alkoxy; and wherein R^(m) and         R^(n) are independently selected from hydrogen or —C₁₋₃alkyl.

In some embodiments, R³ is

-   -   Hydrogen;     -   Methyl, 1-methoxyethyl, 2-hydroxypropan-2-yl, 1-methoxyethyl, or         (2,4-dioxothiazolidin-3-yl)methyl;     -   Isopropoxy, methoxy-d3, methoxy, ethoxy, difluoromethoxy,         2-methoxyethoxy, 2-methoxy-2-methylpropoxy,         2-hydroxy-2-methylpropoxy, cyclopropylmethoxy,         (1,4-dioxan-2-yl)methoxy, (4-hydroxycyclohexyl)oxy,         (cis-4-hydroxycyclohexyl)oxy, (trans-4-hydroxycyclohexyl)oxy,         (4-methoxycyclohexyl)oxy, (cis-4-methoxycyclohexyl)oxy,         (trans-4-methoxycyclohexyl)oxy, or (3-methyloxetan-3-yl)methoxy;     -   cyano     -   3-methoxycyclobutyl, (trans)-3-methoxycyclobutyl,         (cis)-3-methoxycyclobutyl, 2,2-dichlorocyclopropyl, or         1-cyanocyclopropyl;     -   Morpholino, 3-methyl-morpholino, 3(R)-methyl-morpholino,         3(S)-methyl-morpholino, 3,3-dimethylmorpho;     -   tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl,         (R)-tetrahydro-2H-pyran-3-yl, (S)-tetrahydro-2H-pyran-3-yl,         2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl;     -   3-methoxypyrrolidin-1-yl, 3(R)-methoxypyrrolidin-1-yl,         3(S)-methoxypyrrolidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl,         3-(2-hydroxyethoxy)pyrrolidin-1-yl,         3-(trifluoromethoxy)pyrrolidin-1-yl,         3(R)-(trifluoromethoxy)pyrrolidin-1-yl,         3(S)-(trifluoromethoxy)pyrrolidin-1-yl,         2-(aminocarbonyl)pyrrolidin-1-yl,         2(R)-(aminocarbonyl)pyrrolidin-1-yl,         2(S)-(aminocarbonyl)pyrrolidin-1-yl,         3-(methoxymethyl)pyrrolidin-1-yl,         3(R)-(methoxymethyl)pyrrolidin-1-yl,         3(S)-(methoxymethyl)pyrrolidin-1-yl,         3-cyano-4-hydroxypyrrolidin-1-yl,         cis-3-cyano-4-hydroxypyrrolidin-1-yl,         trans-3-cyano-4-hydroxypyrrolidin-1-yl,         3-cyano-4-methoxypyrrolidin-1-yl,         cis-3-cyano-4-methoxypyrrolidin-1-yl,         trans-3-cyano-4-methoxypyrrolidin-1-yl,         2-(methoxymethyl)pyrrolidin-1-yl,         2(R)-(methoxymethyl)pyrrolidin-1-yl,         2(S)-(methoxymethyl)pyrrolidin-1-yl, 3-methylpyrrolidin-1-yl,         3(R)-methylpyrrolidin-1-yl, 3(S)-methylpyrrolidin-1-yl,         pyrrolidin-1-yl, 3-(cyanomethoxy)pyrrolidin-1-yl;     -   5-azaspiro[2.4]heptan-5-yl;     -   tetrahydrofuran-3-yl;     -   3-methoxyazetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl;     -   1,4-dioxan-2-yl;     -   4-aminotetrahydro-2H-pyran-4-yl,         4-(aminomethyl)tetrahydro-2H-pyran-4-yl,     -   4-methoxypiperidin-1-yl, 4-hydroxy-4-methylpiperidin-1-yl,         1-(2,2,2-trifluoroethyl)piperidin-4-yl, 3-methoxypiperidin-1-yl,         3(R)-methoxypiperidin-1-yl, 3(S)-methoxypiperidin-1-yl,         3-ethoxypiperidin-1-yl, 3(R)-ethoxypiperidin-1-yl,         3(S)-ethoxypiperidin-1-yl;     -   3-cyano-2-azabicyclo[3.1.0]hexan-2-yl,         (3R)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl,         (3S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl,         3-azabicyclo[3.1.0]hexan-3-yl; 4-methylpyridin-3-yl,         5-methylpyridazin-4-yl, 5-methoxypyridazin-4-yl,         3,5-dimethylisoxazol-4-yl, 4-methoxypyridin-3-yl,         4-(2-hydroxypropan-2-yl)pyridin-3-yl, 6-cyanopyridin-3-yl,         4-cyanopyridin-3-yl, 2-cyanopyridin-3-yl, 3-methylpyrazin-2-yl,         5-cyanopyridazin-4-yl, 5-fluoropyridazin-4-yl,         4-fluoropyridin-3-yl, 4-isopropylpyridin-3-yl,         4-(1-hydroxyethyl)pyridin-3-yl, 4-(1-methoxyethyl)pyridin-3-yl,         pyridin-2-yl, or thiazol-4-yl.

In some embodiments, (R¹ and R²), or (R² and R³), or (R³ and R⁴), together with the atoms to which they are attached, form a fused 5- to 7-membered ring system, said fused ring system comprises 0-2 oxygen heteroatoms as ring member(s) and is optionally and independently substituted with halogen, —C₁₋₆ alkyl, —C₁₋₆alkoxy, -haloC₁₋₆alkyl, -haloC₁₋₆alkoxy, or —C₃₋₆cycloalkyl.

In some embodiments, R¹ and R², together with the atoms to which they are attached, form a fused ring system selected from

or R² and R³, together with the atoms to which they are attached, form a fused ring system

R³ and R⁴, together with the atoms to which they are attached, form a fused ring system selected from

and wherein each of fused ring system is optionally and independently substituted with halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, -haloC₁₋₆alkyl, -haloC₁₋₆alkoxy, or —C₃₋₆cycloalkyl.

In some embodiments, Cy¹ is

-   -   a 5- to 7-membered monocyclic heterocyclyl or heteroaryl         comprising 1, 2, 3 or 4 heteroatoms selected from oxygen,         nitrogen or sulfur as ring member(s), or     -   7- to 14-membered bicyclic or tricyclic heterocyclyl or         heteroaryl having 1, 2, or 3 heteroatoms selected from oxygen,         nitrogen or sulfur as ring member(s), each of which is         optionally substituted with at least one substituent R^(i).

In some embodiments, Cy¹ is

-   -   said 5- to 7-membered monocyclic heteroaryl comprising 1, 2, 3         or 4 heteroatom(s) selected from oxygen (O), nitrogen (N) or         sulfur (S) as ring member(s), preferably pyrazolyl, triazolyl,         imidazolyl, thiazolyl, oxazolyl, furanyl, pyridinyl,         pyridazinyl, pyrazinyl or pyrimidinyl, said monocyclic         heteroaryl is optionally substituted with one or two         substituents selected from         i. halogen;         ii. cyano;         iii. —C₁₋₆alkyl optionally substituted with halogen, hydroxy,         —C₁₋₆alkoxy, —C(O)R^(m) (preferably R^(m) is morpholinyl), or         —NR^(m)R^(n);         iv. heterocyclyl optionally substituted with halogen,         C₁₋₆alkyl-, —C₁₋₆alkyl substituted with —C₁₋₆alkoxy, or oxo;         preferably said heterocyclyl is selected from tetrahydrofuranyl         (preferably tetrahydrofuran-3-yl), morpholinyl (preferably         morpholino), 2-oxa-5-azabicyclo[2.2.1]heptanyl (preferably         2-oxa-5-azabicyclo[2.2.1]heptan-2-yl),         8-oxa-3-azabicyclo[3.2.1]octanyl (preferably         8-oxa-3-azabicyclo[3.2.1]octan-8-yl), isoindolinyl (preferably         isoindolin-2-yl), each of which is optionally substituted with         methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, n-butyl,         methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, or oxo;         v. —C₃₋₆cycloalkyl optionally substituted with halogen, -oxo,         —C₁₋₆alkyl, C₁₋₆alkoxy-, or —C₁₋₆alkyl substituted with         —C₁₋₆alkoxy; or         vi. —OR^(j), wherein R^(j) is —C₁₋₆alkyl, —C₁₋₆alkyl substituted         with —C₁₋₆alkoxy, or heterocyclyl;         vii. oxo;     -   said 7- to 14-membered bicyclic or tricyclic heteroaryl         comprising 1, 2, or 3 heteroatom(s) as ring member(s),         preferably benzoimidazolyl, imidazopyrimidinyl,         pyrazolopyrazinyl, pyrazolopyrimidinyl, benzothiophenyl,         benzothiazolyl, benzoisoxazolyl, benzooxazolyl,         benzoisothiazolyl, imidazopyridazinyl, imidazopyridazinyl;         dihydro-4H-furo[3,2-c]pyranyl,         6,7-dihydro-4H-thieno[3,2-c]pyranyl,         2,3-dihydropyrazolo[5,1-b]oxazolyl,         4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,         1,3a,4,6,7,7a-hexahydropyrano[4,3-c]pyrazolyl,         4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl,         4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl,         4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl,         4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl,         4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl,         6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl,         2,3-dihydropyrazolo[5,1-b]oxazolyl,         2,3-dihydropyrazolo[5,1-b]oxazolyl,         1,3a,4,6,7,7a-hexahydropyrano[4,3-c]pyrazolyl,         6,7-dihydro-4H-pyrano[4,3-d]thiazolyl,         [1,3]dioxolo[4,5-c]pyridinyl,         2,3-dihydro-[1,4]dioxino[2,3-c]pyridinyl,         3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,         2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl,         2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl,         3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazinyl, or         2H-pyrido[3,2-b][1,4]oxazin-4 (3H)-yl, each of which is         optionally substituted with halogen, —C₁₋₆alkyl, —NH₂, or         —C(O)R^(m), wherein R^(m) is C₁₋₆alkyl.

In some embodiments, Cy¹ is a 7- to 14-membered bicyclic heteroaryl which is a pyridinyl, pyrazolyl, thienyl, or thiazolyl ring fused with a 5- or 6-membered heterocyclyl ring, wherein said 5- or 6-membered heterocyclyl ring comprising one or two heteroatoms selected from oxygen or nitrogen as ring member(s) and said 5- or 6-membered heterocyclyl ring is optionally substituted with one or two C₁₋₆alkyl or oxo, preferably two C₁₋₆alkyl, more preferably two methyl, most preferably two methyl on the same carbon atom. In some embodiments, Cy¹ is a 7- to 14-membered bicyclic heteroaryl which is a pyridinyl ring fused with a 5- or 6-membered heterocyclyl ring, wherein said 5- or 6-membered heterocyclyl ring comprising one or two heteroatoms selected from oxygen (O) or nitrogen (N) as ring member(s) and said 5- or 6-membered heterocyclyl ring is optionally substituted with one or two C₁₋₆alkyl or oxo, preferably two C₁₋₆alkyl, more preferably two methyl, most preferably two methyl on the same carbon atom. In some embodiments, Cy¹ is a 7- to 14-membered bicyclic heteroaryl which is a pyridinyl ring fused with a 5- or 6-membered heterocyclyl ring, wherein said 5- or 6-membered heterocyclyl ring comprising two oxygen atoms as ring member(s) and said 5- or 6-membered heterocyclyl ring is optionally substituted with one or two C₁₋₆alkyl, preferably two C₁₋₆alkyl, more preferably two methyl, most preferably two methyl on the same carbon atom. In some embodiments, Cy¹ is a 7- to 14-membered bicyclic heteroaryl which is a pyridinyl ring fused with 1,4-dioxane ring, wherein said 1,4-dioxane ring is optionally substituted with one or two C₁₋₆alkyl, preferably two C₁₋₆alkyl, more preferably two methyl, most preferably two methyl on the same carbon atom; any of the said alkyl or alkoxy is optionally enriched in deuterium. In some preferred embodiments, Cy¹ is

preferably

In some embodiments, Cy¹ is

In one embodiment, disclosed herein is a compound of Formula (I-B):

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

X is N or CH;

L¹ is a direct bond, —(CR^(a)R^(b))_(q)—, —O—, —S—, —S(O)—, —SO₂—, —C(O)—, C(O)O—, —OC(O)—, —NR^(a)—, —O—(CR^(a)R^(b))_(q), —S—(CR^(a)R^(b)))_(q)—, —S(O)R(CR^(a)R^(b))_(q)—, —SO₂—(CR^(a)R^(b))_(q)—, —C(O)—(CR^(a)R^(b))_(q)—, C(O)O—(CR^(a)R^(b))_(q)—, —OC(O)—(CR^(a)R^(b))_(q)—, —NR^(a)—(CR^(a)R^(b))_(q)—, —C(O)NR^(a)—, —NR^(a)C(O)—, —NR^(a)C(O)O—, —NR^(a)C(O)NR^(b)—, —SO₂NR^(a)—, —NR^(a)SO₂—, —NR^(a)S(O)₂NR^(b)—, —NR^(a)S(O)NR^(b)—, —C(O)NR^(a)SO₂—, —C(O)NR^(a)SO—, or —C(═NR^(a))NR^(b)—, wherein q is a number of 1 to 7, and; R^(a) and R^(b) are independently hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R¹ is —C₁₋₆alkyl, -haloC₁₋₆alkyl, —C₁₋₆alkoxy, -haloC₁₋₆ alkoxyl, —C₃₋₆ cycloalkyl, aryl, or —NR^(c)R^(d); each of R², R³, and R⁴ is independently hydrogen, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl (preferably, morpholin-4-yl, tetrahydrofuran-3-yl), aryl, heteroaryl, oxo, —CN, —NO₂, —OR^(e), —SO₂R^(e), —COR^(e), —CO₂R^(e), —CONR^(e)R^(f), —C(═NR^(e))NR^(f)R^(g), —NR^(e)R^(f), —NR^(e)COR^(f), —NR^(e)CONR^(f)R^(g), —NR^(e)CO₂R^(f), —NR^(e)SONR^(f)R^(g), —NR^(e)SO₂NR^(f)R^(g), or —NR^(e)SO₂R^(f), wherein each of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently and optionally substituted with at least one substituents selected from halogen, hydroxy-C₁₋₆ alkyl (preferably, hydroxymethyl), —OR^(h), or C₁₋₆alkoxy-C₁₋₆alkyl-; wherein R^(h) is hydrogen, alkyl, or heterocyclyl, R^(e), R^(f), and R^(g) are each independently hydrogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with one to three substituents selected from halogen, hydroxy, cyano, —C₁₋₆alkoxy; —C₃₋₆cycloalkyl optionally substituted with halogen, hydroxy, or C₁₋₆alkoxy; R⁵ is hydrogen or C₁₋₆alkyl; Cy¹ is 6- to 12-membered aryl or 5- to 14-membered heteroaryl, or 5- to 14-membered heterocyclyl, each of which is optionally substituted with at least one substituent R^(i), R^(i) is independently halogen, cyano, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO₂, —OR^(j), —SO₂R^(j), —COR^(j), —CO₂R^(k), —CONR^(j)R^(k), —C(═NR^(j))NR^(k)R^(l), —NR^(j)R^(k), —NR^(j)COR^(k), —NR^(j)CONR^(k)R^(l), —NR^(j)CO₂R^(k), —NR^(j)SONR^(k)R^(l), —NR^(j)SO₂NR^(k)R^(l), or —NR^(j)SO₂R^(k), wherein each of said —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, OR^(m), C(O)R^(m), —NR^(m)R^(n), —C₁₋₆alkyl, C₁₋₆alkoxy-, C₁₋₆alkoxy-C₁₋₆alkyl-, or oxo; R^(j), R^(k), R^(l), R^(m), R^(n) are each independently hydrogen, —C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl-, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or (R¹ and R²), or (R² and R³), or (R³ and R⁴), together with the atoms to which they are attached, form a fused ring system, said fused ring system comprises 0-4 heteroatoms selected from oxygen, nitrogen or sulfur as ring member(s) and is optionally and independently substituted with halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, -haloC₁₋₆alkyl, -haloC₁₋₆alkoxy, or —C₃₋₆cycloalkyl; any of the said alkyl or alkoxy can be optionally enriched in deuterium.

In some embodiments, disclosed here is a compound of Formula (I-C)

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:

X is N or CH;

L¹ is a direct bond; R¹ is —C₁₋₆alkyl, or -haloC₁₋₆alkyl; each of R² and R⁴ is independently hydrogen, halogen, —C₁₋₆alkyl or —C₁₋₆alkoxy; R³ is independently hydrogen, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl, -oxo-, —CN, —NO₂, —OR^(e), —SO₂R^(e), —COR^(e), —CO₂R^(e), —CONR^(e)R^(f), —C(—NR^(e))NR^(f)R^(g), —NR^(e)R^(f), —NR^(e)COR^(f), —NR^(e)CONR^(f)R^(g), —NR^(e)CO₂R^(f), —NR^(e)SONR^(f)R^(g), —NR^(e)SO₂NR^(f)R^(g), or —NR^(e)SO₂R^(f), wherein each of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently and optionally substituted with at least one substituents selected from i) cyano, oxo, halogen, —NH₂, —OR^(h), —C(O)NR^(m)R^(n); ii) heterocyclyl optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), substituted or unsubstituted —C₁₋₆alkyl, substituted or unsubstituted —C₁₋₆ alkoxy or —C(O)NR^(m)R^(n); or, iii) C₁₋₆alkyl optionally substituted with halogen, —C₁₋₆alkyl substituted with hydroxy (preferably, hydroxymethyl, hydroxyethyl), —C₁₋₆alkyl substituted with —NH₂, —NH₂ or —C₁₋₆alkyl substituted with C₁₋₆alkoxy; wherein R^(h) is hydrogen, hydroxy, alkyl, substituted with hydroxy, or heterocyclyl, R^(e), R^(f), and R^(g) are each independently hydrogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with one to three substituents selected from halogen, hydroxy, cyano, -oxo-, —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy; —C₃₋₆cycloalkyl optionally substituted with halogen, hydroxy, or C₁₋₆alkoxy, —C(O)NR^(m)R^(n), or heterocyclyl; R⁵ is hydrogen or C₁₋₆alkyl; Cy¹ is a 7- to 14-membered bicyclic or tricyclic heterocyclyl or heteroaryl having 1, 2, or 3 heteroatoms selected from oxygen (O), nitrogen (N) or sulfur (S) as ring member(s), which is optionally substituted with at least one substituent R^(i), R^(i) is independently halogen, cyano, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO₂, —OR^(j), —SO₂R^(j), —COR^(j), —CO₂R^(k), —CONR^(j)R^(k), —C(═NR^(j))NR^(k)R^(l), —NR^(j)R^(k), —NR^(j)COR^(k), —NR^(j)CONR^(k)R^(l), —NR^(j)CO₂R^(k), —NR^(j)SONR^(k)R^(l), —NR^(j)SO₂NR^(k)R^(l), or —NR^(j)SO₂R^(k), wherein each of said —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, OR^(m), C(O)R^(m), —NR^(m)R^(n), —C₁₋₆alkyl, C₁₋₆alkoxy-, C₁₋₆alkyl substituted with —C₁₋₆alkoxy, or oxo; R^(j), R^(k), R^(l), R^(m), R^(n) are each independently hydrogen, —C₁₋₆alkyl, —C₁₋₆alkyl substituted with C₁₋₆alkoxy, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or (R¹ and R²), or (R² and R³), or (R³ and R⁴), together with the atoms to which they are attached, form a fused ring system, said fused ring system comprises 0-4 heteroatoms selected from oxygen (O), nitrogen (N) or sulfur (S) as ring member(s) and is optionally and independently substituted with halogen, —C₁₋₆ alkyl, —C₁₋₆alkoxy, -haloC₁₋₆alkyl, -haloC₁₋₆alkoxy, or —C₃₋₆cycloalkyl; any of the said alkyl or alkoxy is optionally enriched in deuterium.

In some embodiments, R¹ is —C₁₋₃ alkyl, preferably methyl, ethyl, propyl, or isopropyl.

In some embodiments, R² and R⁴ are each independently hydrogen, halogen, —C₁₋₃alkyl, or —C₁₋₃ alkoxy, preferably hydrogen, fluoro, methyl, methoxy, ethoxy, or isopropoxy.

In some embodiments, R³ is

-   -   hydrogen;     -   cyano;     -   halogen;     -   —C₁₋₄ alkyl optionally substituted with at least one substituent         independently selected from halogen, 3- to 6-membered         heterocyclyl or —OR^(h), wherein         3- to 6-membered heterocyclyl comprises one or two heteroatoms         selected from oxygen (O), nitrogen (N) or sulfur (O) as ring         member(s), optionally substituted with at least one substituent         independently selected from cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n),         wherein —C₁₋₆alkyl or —C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy; and         R^(h) is hydrogen, alkyl, or heterocyclyl;     -   —C₃₋₆cycloalkyl, optionally substituted with at least one         substituent independently selected from cyano, -oxo, halogen,         —NR^(m)R^(n), hydroxy, —C₁₋₆alkyl, —C₁₋₆alkoxy or         —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or C₁₋₆ alkoxy is         substituted with at least one substitution independently         selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or         C₁₋₆alkoxy;     -   heterocyclyl comprising one or two heteroatoms selected from         oxygen (O), nitrogen (N) or sulfur (S) as ring member(s),         optionally substituted with at least one substituent         independently selected from cyano, -oxo-, halogen, hydroxy,         C₁₋₆alkyl, alkoxy, —NRR^(m)R^(n), or —C(O)NR^(m)R^(n), and         wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy;     -   —OR^(e), wherein R^(e) is —C₁₋₆alkyl, —C₃₋₆cycloalkyl, 3- to         6-membered heterocyclyl, or aryl, wherein         i) —C₁₋₆alkyl is optionally substituted with cyano, -oxo-,         halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkoxy-, —C₃₋₆cycloalkyl         optionally substituted with cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), —C₁₋₆alkyl, C₁₋₆alkoxy or —C(O)NR^(m)R^(n), 4- to         6-membered heterocyclyl optionally substituted with cyano,         halogen, hydroxy, C₁₋₆alkyl or C₁₋₆alkoxy; and,         ii) —C₃₋₆cycloalkyl or 3- to 6-membered heterocyclyl is         optionally substituted with cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), C₁₋₆alkyl, C₁₋₆alkoxy or —C(O)NR^(m)R^(n), wherein         —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one         substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy;     -   —C₅₋₁₀aryl; or     -   heteroaryl comprising one oxygen (O), nitrogen (N) or sulfur (S)         heteroatom as ring member, optionally substituted with at least         one substitution independently selected from cyano, -oxo,         halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or         —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or C₁₋₆alkoxy is         substituted with at least one substitution independently         selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or         C₁₋₆alkoxy;         and wherein R^(m) and R^(n) are independently selected from         hydrogen or C₁₋₃alkyl;         any of the said alkyl or alkoxy is optionally enriched in         deuterium.         In some preferred embodiments, R³ is heterocyclyl comprising one         or two heteroatoms selected from oxygen (O), nitrogen (N) or         sulfur (S) as ring member(s), optionally substituted with at         least one substituent independently selected from cyano, -oxo-,         halogen, hydroxy, C₁₋₆alkyl, alkoxy, —NRR^(m)R^(n), or         —C(O)NR^(m)R^(n), and wherein —C₁₋₆alkyl or C₁₋₆alkoxy is         substituted with at least one substitution independently         selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or         C₁₋₆alkoxy.

In some embodiments, R³ is

-   -   hydrogen;     -   cyano;     -   halogen;     -   —C₁₋₄ alkyl optionally substituted with at least one substituent         independently selected from halogen, 3- to 6-membered         heterocyclyl or —OR^(h), wherein         Said 3- to 6-membered heterocyclyl comprises one or two         heteroatoms selected from oxygen (O), nitrogen (N) or sulfur (O)         as ring member(s), optionally substituted with at least one         substituent independently selected from cyano, -oxo, halogen,         hydroxy, —NR^(m)R^(n), C₁₋₆alkyl, —C₁₋₆alkoxy or         —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or C₁₋₆alkoxy is         substituted with at least one substitution independently         selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or         C₁₋₆alkoxy, and,         R^(h) is hydrogen, alkyl or heterocyclyl (preferably 3- to         6-membered heterocyclyl, e.g., tetrahydrofuranyl,         thiazolidinyl);     -   —C₃₋₆cycloalkyl, optionally substituted with at least one         substituent independently selected from cyano, -oxo, halogen,         —NR^(m)R^(n), hydroxy, —C₁₋₆alkyl, —C₁₋₆alkoxy or         —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or C₁₋₆alkoxy is         substituted with at least one substitution independently         selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or         C₁₋₆alkoxy;     -   heterocyclyl, preferably 4- to 6-membered monocyclic saturated         heterocyclyl, saturated mono-spiro heterocyclyl, saturated         bicyclic fused heterocyclyl, or saturated bridged heterocyclyl,         comprising one or two heteroatoms selected from oxygen (O),         nitrogen (N) or sulfur (S) as ring member(s), more preferably         morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl,         1,4-dioxanyl, piperidinyl or azetidinyl, optionally substituted         with at least one substituent independently selected from cyano,         -oxo, halogen, hydroxy, —C₁₋₆alkyl, alkoxy, —NR^(m)R^(n), or         —C(O)NR^(m)R^(n), and wherein —C₁₋₆alkyl or —C₁₋₆alkoxy is         substituted with at least one substitution independently         selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or         C₁₋₆alkoxy;     -   —OR^(e), wherein R^(e) is —C₁₋₆alkyl, —C₃₋₆cycloalkyl, 3- to         6-membered heterocyclyl (preferably 4- to 6-membered monocyclic         saturated heterocyclyl comprising one oxygen heteroatom as ring         member), or aryl, wherein         i) —C₁₋₆alkyl is optionally substituted with cyano, -oxo-,         halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkoxy-, —C₃₋₆cycloalkyl         optionally substituted with cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), —C₁₋₆alkyl, C₁₋₆alkoxy or —C(O)NR^(m)R^(n), 4- to         6-membered heterocyclyl optionally substituted with cyano,         halogen, hydroxy, —C₁₋₆alkyl or —C₁₋₆alkoxy; and,         ii) —C₃₋₆cycloalkyl or 3- to 6-membered heterocyclyl is         optionally substituted with cyano, -oxo, halogen, hydroxy,         NR^(m)R^(n), C₁₋₆alkyl, C₁₋₆alkoxy or —C(O)NR^(m)R^(n), wherein         —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one         substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆ alkyl or C₁₋₆alkoxy;     -   —C₅₋₁₀aryl; or     -   heteroaryl, preferably 5- to 6-membered heteroaryl comprising         one oxygen (O), nitrogen (N) or sulfur (S) heteroatom as ring         member, optionally substituted with at least one substitution         independently selected from cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n),         wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy;         and wherein R^(m) and R^(n) are independently selected from         hydrogen or C₁₋₃alkyl.         In some preferred embodiments, R³ is heterocyclyl, preferably 4-         to 6-membered monocyclic saturated heterocyclyl, saturated         mono-spiro heterocyclyl, saturated bicyclic fused heterocyclyl,         or saturated bridged heterocyclyl, comprising one or two         heteroatoms selected from oxygen (O), nitrogen (N) or sulfur (S)         as ring member(s), more preferably morpholinyl,         tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl,         1,4-dioxanyl, piperidinyl or azetidinyl, optionally substituted         with at least one substituent independently selected from cyano,         -oxo, halogen, hydroxy, —C₁₋₆alkyl, alkoxy, —NR^(m)R^(n), or         —C(O)NR^(m)R^(n), and wherein —C₁₋₆alkyl or —C₁₋₆alkoxy is         substituted with at least one substitution independently         selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or         C₁₋₆alkoxy.

In some embodiments, R³ is

-   -   hydrogen, cyano, halogen;     -   —C₁₋₄ alkyl optionally substituted with at least one substituent         independently selected from halogen, 3- to 6-membered         heterocyclyl or —OR^(h), wherein         Said 3- to 6-membered heterocyclyl is selected from morpholinyl,         tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl,         1,4-dioxanyl, piperidinyl, thiazolidinyl or azetidinyl, each of         which is optionally substituted with at least one substituent         independently selected from cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), C₁₋₆ alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n),         wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy, and, R^(h) is hydrogen,         C₁₋₆alkyl or 3- to 6-membered heterocyclyl (e.g.,         tetrahydrofuranyl or thiazolidinyl);     -   —C₃₋₆cycloalkyl, optionally substituted with at least one         substituent independently selected from cyano, -oxo, halogen,         NR^(m)R^(n), hydroxy, —C₁₋₆alkyl, —C₁₋₆alkoxy or         —C(O)NR^(m)R^(n), hydroxy, or C₁₋₆alkoxy, wherein —C₁₋₆alkyl or         C₁₋₆alkoxy is substituted with at least one substitution         independently selected from cyano, halogen, hydroxy, —NH₂,         —C₁₋₆alkyl or C₁₋₆alkoxy;     -   heterocyclyl is selected from morpholinyl, tetrahydrofuranyl,         tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl or         azetidinyl, optionally substituted with at least one substituent         independently selected from cyano, -oxo, halogen, hydroxy,         C₁₋₆alkyl, alkoxy, —NRR^(m)R^(n), or —C(O)NR^(m)R^(n), and         wherein —C₁₋₆alkyl or —C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or —C₁₋₆alkoxy;     -   —OR^(e), wherein R^(e) is —C₁₋₆alkyl, —C₃₋₆cycloalkyl, 4- to         6-membered monocyclic saturated heterocyclyl comprising one         oxygen heteroatom as ring member, or C₆₋₁₀aryl, wherein         i) —C₁₋₆alkyl is optionally substituted with cyano, -oxo-,         halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkoxy-, —C₃₋₆cycloalkyl         optionally substituted with cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n), 4- to         6-membered heterocyclyl optionally substituted with cyano,         halogen, hydroxy, —C₁₋₆alkyl or —C₁₋₆alkoxy; and,         ii) —C₃₋₆cycloalkyl or 3- to 6-membered heterocyclyl is         optionally substituted with cyano, -oxo, halogen, hydroxy,         NR^(m)R^(n), C₁₋₆alkyl, C₁₋₆alkoxy or —C(O)NR^(m)R^(n), wherein         —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one         substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy;     -   —C₆₋₁₀aryl; or     -   5- to 6-membered heteroaryl selected from pyridinyl,         pyridazinyl, pyrazinyl, thiazolyl or isoxazolyl, each of which         is optionally substituted with at least one substitution         independently selected from cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n),         wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy;         and wherein R^(m) and R^(n) are independently selected from         hydrogen or —C₁₋₃alkyl.         In some preferred embodiments, R³ is heterocyclyl is selected         from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl,         pyrrolidinyl, 1,4-dioxanyl, piperidinyl or azetidinyl,         optionally substituted with at least one substituent         independently selected from cyano, -oxo, halogen, hydroxy,         C₁₋₆alkyl, alkoxy, —NRR^(m)R^(n), or —C(O)NR^(m)R^(n), and         wherein —C₁₋₆alkyl or —C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or —C₁₋₆alkoxy.

In some embodiments, R³ is

-   -   hydrogen, cyano, halogen;     -   —C₁₋₄ alkyl optionally substituted with at least one substituent         independently selected from halogen, hydroxy, C₁₋₃alkoxy,         thiazolidin-3-yl optionally substituted with at least one         substituent independently selected from cyano, -oxo, halogen,         hydroxy, —NR^(m)R^(n), or —C₁₋₃alkyl;     -   —C₃₋₆cycloalkyl, optionally substituted with at least one         substituent independently selected from cyano, -oxo, halogen,         —NR^(m)R^(n), hydroxy, —C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein         —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one         substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or —C₁₋₃alkoxy;     -   heterocyclyl is selected from morpholinyl, tetrahydrofuranyl,         tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl or         azetidinyl, optionally substituted with at least one substituent         independently selected from cyano, -oxo, halogen, hydroxy,         C₁₋₆alkyl, alkoxy, —NR^(m)R^(n), or —C(O)NR^(m)R^(n), and         wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or —C₁₋₆alkoxy;     -   —OR^(e), wherein R is —C₁₋₆alkyl, —C₃₋₆cycloalkyl, 4- to         6-membered monocyclic saturated heterocyclyl comprising one         oxygen heteroatom as ring member, or C₆₋₁₀aryl, wherein         i) —C₁₋₆alkyl is optionally substituted with cyano, -oxo-,         halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkoxy-, —C₃₋₆cycloalkyl         optionally substituted with cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n), 4- to         6-membered heterocyclyl optionally substituted with cyano,         halogen, hydroxy, —C₁₋₆alkyl or —C₁₋₆alkoxy; and,         ii) —C₃₋₆cycloalkyl or 3- to 6-membered heterocyclyl is         optionally substituted with cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n),         wherein —C₁₋₆alkyl or —C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or —C₁₋₆alkoxy;     -   —C₆₋₁₀aryl; or     -   5- to 6-membered heteroaryl selected from pyridinyl,         pyridazinyl, pyrazinyl, thiazolyl or isoxazolyl, each of which         is optionally substituted with at least one substitution         independently selected from cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n),         wherein —C₁₋₆alkyl or —C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or —C₁₋₆alkoxy;         and wherein R^(m) and R^(n) are independently selected from         hydrogen or —C₁₋₃alkyl.         In some preferred embodiments, R³ is heterocyclyl is selected         from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl,         pyrrolidinyl, 1,4-dioxanyl, piperidinyl or azetidinyl,         optionally substituted with at least one substituent         independently selected from cyano, -oxo, halogen, hydroxy,         C₁₋₆alkyl, alkoxy, —NR^(m)R^(n), or —C(O)NR^(m)R^(n), and         wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₆alkyl or —C₁₋₆alkoxy

In some embodiments, R³ is

-   -   hydrogen, cyano, halogen;     -   methyl, ethyl, propyl or butyl, each of which optionally         substituted with at least one substituent independently selected         from halogen, hydroxy, methoxy, ethoxy, propoxy, or         2,4-dioxothiazolidin-3-yl;     -   cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of         which is optionally substituted with at least one substituent         independently selected from cyano, -oxo, halogen, —NR^(m)R^(n),         hydroxy, —C₁₋₃alkyl, or —C₁₋₃alkoxy, wherein —C₁₋₃alkyl or         C₁₋₃alkoxy is optionally substituted with at least one         substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₃alkyl or —C₁₋₃alkoxy;     -   heterocyclyl is selected from morpholin-2-yl, morpholin-3-yl,         morpholin-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,         tetrahydropyran-2-yl, tetrahydropyran-3-yl,         tetrahydropyran-4-yl, pyrrolidine-1-yl, pyrrolidin-2-yl,         pyrrolidin-3-yl, 1,4-dioxan-2-yl, piperidin-1-yl,         piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, azetidin-1-yl,         azetidine-2-yl, azetidin-3-yl, 5-azaspiro[2.4]heptanyl,         3-azabicyclo[3.1.0]hexan-3-yl or 2-azabicyclo[3.1.0]hexan-2-yl,         each of which is optionally substituted with at least one         substituent independently selected from cyano, -oxo, halogen,         hydroxy, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NR^(m)R^(n), or         —C(O)NR^(m)R^(n), and wherein —C₁₋₆alkyl or C₁₋₆alkoxy is         substituted with at least one substitution independently         selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or         —C₁₋₆alkoxy;     -   —OR^(e), wherein R^(e) is         i) methyl, ethyl, propyl (iso-propyl), butyl, pentyl or hexyl,         each of which is optionally substituted with deuterium, cyano,         -oxo-, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₃alkoxy-,         —C₃₋₆cycloalkyl optionally substituted with cyano, -oxo,         halogen, hydroxy, —NR^(m)R^(n), —C₁₋₃alkyl, —C₁₋₃alkoxy or         —C(O)NR^(m)R^(n), or 4- to 6-membered heterocyclyl optionally         substituted with cyano, halogen, hydroxy, —C₁₋₃alkyl or         —C₁₋₃alkoxy; or,         ii) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,         morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,         tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,         tetrahydropyran-2-yl, tetrahydropyran-3-yl,         tetrahydropyran-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,         pyrrolidin-3-yl, 1,4-dioxan-2-yl, piperidin-1-yl,         piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, azetidin-1-yl,         azetidine-2-yl or azetidin-3-yl, each of which is optionally         substituted with cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n),         —C₁₋₃alkyl, —C₁₋₃alkoxy or —C(O)NR^(m)R^(n), wherein —C₁₋₃alkyl         or —C₁₋₃alkoxy is substituted with at least one substitution         independently selected from cyano, halogen, hydroxy, —NH₂,         —C₁₋₃alkyl or —C₁₋₃alkoxy;     -   —C₆₋₁₀aryl; or     -   5- to 6-membered heteroaryl selected from pyridin-1-yl,         pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-1-yl,         pyridazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-1-yl,         pyrazin-2-yl, thiazol-2-yl, thiazol-3-yl, thiazol-4-yl,         isoxazol-2-yl, isoxazol-3-yl or isoxazol-4-yl, each of which is         optionally substituted with at least one substitution         independently selected from cyano, -oxo, halogen, hydroxy,         —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₃alkoxy or —C(O)NR^(m)R^(n),         wherein —C₁₋₃alkyl or —C₁₋₃alkoxy is substituted with at least         one substitution independently selected from cyano, halogen,         hydroxy, —NH₂, —C₁₋₃alkyl or C₁₋₃alkoxy; and wherein R^(m) and         R^(n) are independently selected from hydrogen or —C₁₋₃alkyl.         In some preferred embodiments, R³ is heterocyclyl is selected         from morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,         tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,         tetrahydropyran-2-yl, tetrahydropyran-3-yl,         tetrahydropyran-4-yl, pyrrolidine-1-yl, pyrrolidin-2-yl,         pyrrolidin-3-yl, 1,4-dioxan-2-yl, piperidin-1-yl,         piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, azetidin-1-yl,         azetidine-2-yl, azetidin-3-yl, 5-azaspiro[2.4]heptanyl,         3-azabicyclo[3.1.0]hexan-3-yl or 2-azabicyclo[3.1.0]hexan-2-yl,         each of which is optionally substituted with at least one         substituent independently selected from cyano, -oxo, halogen,         hydroxy, —C₁₋₆alkyl, —C₁₋₆alkoxy, —NR^(m)R^(n), or         —C(O)NR^(m)R^(n), and wherein —C₁₋₆alkyl or C₁₋₆alkoxy is         substituted with at least one substitution independently         selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or         —C₁₋₆alkoxy

In some embodiments, R³ is

-   -   Hydrogen;     -   Methyl, 1-methoxyethyl, 2-hydroxypropan-2-yl, 1-methoxyethyl, or         (2,4-dioxothiazolidin-3-yl)methyl;     -   Isopropoxy, methoxy-d3, methoxy, ethoxy, difluoromethoxy,         2-methoxyethoxy, 2-methoxy-2-methylpropoxy,         2-hydroxy-2-methylpropoxy, cyclopropylmethoxy,         (1,4-dioxan-2-yl)methoxy, (4-hydroxycyclohexyl)oxy,         (cis-4-hydroxycyclohexyl)oxy, (trans-4-hydroxycyclohexyl)oxy,         (4-methoxycyclohexyl)oxy, (cis-4-methoxycyclohexyl)oxy,         (trans-4-methoxycyclohexyl)oxy, or (3-methyloxetan-3-yl)methoxy;     -   cyano     -   3-methoxycyclobutyl, (trans)-3-methoxycyclobutyl,         (cis)-3-methoxycyclobutyl, 2,2-dichlorocyclopropyl, or         1-cyanocyclopropyl;     -   Morpholino, 3-methyl-morpholino, 3(R)-methyl-morpholino,         3(S)-methyl-morpholino;     -   tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl,         (R)-tetrahydro-2H-pyran-3-yl, (S)-tetrahydro-2H-pyran-3-yl,         2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl, 3,3-dimethylmorpho;     -   3-methoxypyrrolidin-1-yl, 3(R)-methoxypyrrolidin-1-yl,         3(S)-methoxypyrrolidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl,         3-(2-hydroxyethoxy)pyrrolidin-1-yl,         3-(trifluoromethoxy)pyrrolidin-1-yl,         3(R)-(trifluoromethoxy)pyrrolidin-1-yl,         3(S)-(trifluoromethoxy)pyrrolidin-1-yl,         2-(aminocarbonyl)pyrrolidin-1-yl,         2(R)-(aminocarbonyl)pyrrolidin-1-yl,         2(S)-(aminocarbonyl)pyrrolidin-1-yl,         3-(methoxymethyl)pyrrolidin-1-yl,         3(R)-(methoxymethyl)pyrrolidin-1-yl,         3(S)-(methoxymethyl)pyrrolidin-1-yl,         3-cyano-4-hydroxypyrrolidin-1-yl,         cis-3-cyano-4-hydroxypyrrolidin-1-yl,         trans-3-cyano-4-hydroxypyrrolidin-1-yl,         3-cyano-4-methoxypyrrolidin-1-yl,         cis-3-cyano-4-methoxypyrrolidin-1-yl,         trans-3-cyano-4-methoxypyrrolidin-1-yl,         2-(methoxymethyl)pyrrolidin-1-yl,         2(R)-(methoxymethyl)pyrrolidin-1-yl,         2(S)-(methoxymethyl)pyrrolidin-1-yl, 3-methylpyrrolidin-1-yl,         3(R)-methylpyrrolidin-1-yl, 3(S)-methylpyrrolidin-1-yl,         pyrrolidin-1-yl, 3-(cyanomethoxy)pyrrolidin-1-yl;     -   5-azaspiro[2.4]heptan-5-yl;     -   tetrahydrofuran-3-yl;     -   3-methoxyazetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl;     -   1,4-dioxan-2-yl;     -   4-aminotetrahydro-2H-pyran-4-yl,         4-(aminomethyl)tetrahydro-2H-pyran-4-yl,     -   4-methoxypiperidin-1-yl, 4-hydroxy-4-methylpiperidin-1-yl,         1-(2,2,2-trifluoroethyl)piperidin-4-yl, 3-methoxypiperidin-1-yl,         3(R)-methoxypiperidin-1-yl, 3(S)-methoxypiperidin-1-yl,         3-ethoxypiperidin-1-yl, 3(R)-ethoxypiperidin-1-yl,         3(S)-ethoxypiperidin-1-yl;     -   3-cyano-2-azabicyclo[3.1.0]hexan-2-yl,         (3R)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl,         (3S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl,         3-azabicyclo[3.1.0]hexan-3-yl;     -   4-methylpyridin-3-yl, 5-methylpyridazin-4-yl,         5-methoxypyridazin-4-yl, 3,5-dimethylisoxazol-4-yl,         4-methoxypyridin-3-yl, 4-(2-hydroxypropan-2-yl)pyridin-3-yl,         6-cyanopyridin-3-yl, 4-cyanopyridin-3-yl, 2-cyanopyridin-3-yl,         3-methylpyrazin-2-yl, 5-cyanopyridazin-4-yl,         5-fluoropyridazin-4-yl, 4-fluoropyridin-3-yl,         4-isopropylpyridin-3-yl, 4-(1-hydroxyethyl)pyridin-3-yl,         4-(1-methoxyethyl)pyridin-3-yl, pyridin-2-yl, or thiazol-4-yl.

In some preferred embodiments, R³ is

-   -   Morpholino, 3-methyl-morpholino, 3(R)-methyl-morpholino,         3(S)-methyl-morpholino;     -   tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl,         (R)-tetrahydro-2H-pyran-3-yl, (S)-tetrahydro-2H-pyran-3-yl,         2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl;     -   3-methoxypyrrolidin-1-yl, 3(R)-methoxypyrrolidin-1-yl,         3(S)-methoxypyrrolidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl,         3-(2-hydroxyethoxy)pyrrolidin-1-yl,         3-(trifluoromethoxy)pyrrolidin-1-yl,         3(R)-(trifluoromethoxy)pyrrolidin-1-yl,         3(S)-(trifluoromethoxy)pyrrolidin-1-yl,         2-(aminocarbonyl)pyrrolidin-1-yl,         2(R)-(aminocarbonyl)pyrrolidin-1-yl,         2(S)-(aminocarbonyl)pyrrolidin-1-yl,         3-(methoxymethyl)pyrrolidin-1-yl,         3(R)-(methoxymethyl)pyrrolidin-1-yl,         3(S)-(methoxymethyl)pyrrolidin-1-yl,         3-cyano-4-hydroxypyrrolidin-1-yl,         cis-3-cyano-4-hydroxypyrrolidin-1-yl,         trans-3-cyano-4-hydroxypyrrolidin-1-yl,         3-cyano-4-methoxypyrrolidin-1-yl,         cis-3-cyano-4-methoxypyrrolidin-1-yl,         trans-3-cyano-4-methoxypyrrolidin-1-yl,         2-(methoxymethyl)pyrrolidin-1-yl,         2(R)-(methoxymethyl)pyrrolidin-1-yl,         2(S)-(methoxymethyl)pyrrolidin-1-yl, 3-methylpyrrolidin-1-yl,         3(R)-methylpyrrolidin-1-yl, 3(S)-methylpyrrolidin-1-yl,         pyrrolidin-1-yl, 3-(cyanomethoxy)pyrrolidin-1-yl;     -   5-azaspiro[2.4]heptan-5-yl;     -   tetrahydrofuran-3-yl;     -   3-methoxyazetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl;     -   1,4-dioxan-2-yl;     -   4-aminotetrahydro-2H-pyran-4-yl,         4-(aminomethyl)tetrahydro-2H-pyran-4-yl,     -   4-methoxypiperidin-1-yl, 4-hydroxy-4-methylpiperidin-1-yl,         1-(2,2,2-trifluoroethyl)piperidin-4-yl, 3-methoxypiperidin-1-yl,         3(R)-methoxypiperidin-1-yl, 3(S)-methoxypiperidin-1-yl,         3-ethoxypiperidin-1-yl, 3(R)-ethoxypiperidin-1-yl,         3(S)-ethoxypiperidin-1-yl;     -   3-cyano-2-azabicyclo[3.1.0]hexan-2-yl,         (3R)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl,         (3S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl, or         3-azabicyclo[3.1.0]hexan-3-yl.         In some further preferred embodiments, R³ is morpholino,         3-methyl-morpholino, 3(R)-methyl-morpholino, or         3(S)-methyl-morpholino.

In some embodiments, (R¹ and R²), or (R² and R³), or (R³ and R⁴), together with the atoms to which they are attached, form a fused 5- to 7-membered ring system, said fused ring system comprises 0-2 oxygen heteroatoms as ring member(s) and is optionally and independently substituted with halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, -haloC₁₋₆alkyl, -haloC₁₋₆alkoxy, or —C₃₋₆cycloalkyl.

In some embodiments, R¹ and R², together with the atoms to which they are attached, form a fused ring system selected from

or R² and R³, together with the atoms to which they are attached, form a fused ring system

R³ and R⁴, together with the atoms to which they are attached, form a fused ring system selected from

and wherein each of fused ring system is optionally and independently substituted with halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, -haloC₁₋₆alkyl, -haloC₁₋₆alkoxy, or —C₃₋₆cycloalkyl.

In some embodiments, Cy¹ is

-   -   said 7- to 14-membered bicyclic or tricyclic heteroaryl         comprising 1, 2, or 3 heteroatom(s) selected from oxygen,         nitrogen or sulfur as ring member(s), preferably         benzoimidazolyl, imidazopyrimidinyl, pyrazolopyrazinyl,         pyrazolopyrimidinyl, benzothiophenyl, benzothiazolyl,         benzoisoxazolyl, benzooxazolyl, benzoisothiazolyl,         imidazopyridazinyl, imidazopyridazinyl;         dihydro-4H-furo[3,2-c]pyranyl,         6,7-dihydro-4H-thieno[3,2-c]pyranyl,         2,3-dihydropyrazolo[5,1-b]oxazolyl,         4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,         1,3a,4,6,7,7a-hexahydropyrano[4,3-c]pyrazolyl,         4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl,         4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl,         4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl,         4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl,         4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl,         6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl,         2,3-dihydropyrazolo[5,1-b]oxazolyl,         2,3-dihydropyrazolo[5,1-b]oxazolyl,         1,3a,4,6,7,7a-hexahydropyrano[4,3-c]pyrazolyl,         6,7-dihydro-4H-pyrano[4,3-d]thiazolyl,         [1,3]dioxolo[4,5-c]pyridinyl,         2,3-dihydro-[1,4]dioxino[2,3-c]pyridinyl,         3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,         2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl,         2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl,         3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazinyl, or         2H-pyrido[3,2-b][1,4]oxazin-4 (3H)-yl, each of which is         optionally substituted with halogen, —C₁₋₆alkyl, —NH₂, or         —C(O)R^(m), wherein R^(m) is C₁₋₆alkyl; any of the said alkyl is         optionally enriched in deuterium.

In some embodiments, Cy¹ is a 7- to 14-membered bicyclic heteroaryl which is a pyridinyl, pyrazolyl, thienyl, or thiazolyl ring fused with a 5- or 6-membered heterocyclyl ring, wherein said 5- or 6-membered heterocyclyl ring comprising one or two heteroatoms selected from oxygen or nitrogen as ring member(s) and said 5- or 6-membered heterocyclyl ring is optionally substituted with one or two C₁₋₆alkyl or oxo, preferably two C₁₋₆alkyl, more preferably two methyl, most preferably two methyl on the same carbon atom. In some embodiments, Cy¹ is a 7- to 14-membered bicyclic heteroaryl which is a pyridinyl ring fused with a 5- or 6-membered heterocyclyl ring, wherein said 5- or 6-membered heterocyclyl ring comprising one or two heteroatoms selected from oxygen or nitrogen as ring member(s) and said 5- or 6-membered heterocyclyl ring is optionally substituted with one or two C₁₋₆alkyl or oxo, preferably two C₁₋₆alkyl, more preferably two methyl, most preferably two methyl on the same carbon atom. In some embodiments, Cy¹ is a 7- to 14-membered bicyclic heteroaryl which is a pyridinyl ring fused with a 5- or 6-membered heterocyclyl ring, wherein said 5- or 6-membered heterocyclyl ring comprising two oxygen atoms as ring member(s) and said 5- or 6-membered heterocyclyl ring is optionally substituted with one or two C₁₋₆alkyl, preferably two C₁₋₆alkyl, more preferably two methyl, most preferably two methyl on the same carbon atom. In some embodiments, Cy¹ is a 7- to 14-membered bicyclic heteroaryl which is a pyridinyl ring fused with 1,4-dioxane ring, wherein said 1,4-dioxane ring is optionally substituted with one or two C₁₋₆alkyl, preferably two C₁₋₆alkyl, more preferably two methyl most preferably two methyl on the same carbon atom. In some preferred embodiments, Cy¹ is

preferably

In some embodiments, Cy¹ is

In some embodiments, the compound is selected from the exemplified compounds in Examples.

In the second aspect, disclosed herein provides a pharmaceutical composition comprising one or more compounds in the present disclosure or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In the third aspect, disclosed herein provides a method for treating a disease associated with undesirable TYK2 activity (TYK2-related diseases), comprising administrating to a subject in need of such treatment a therapeutically effective amount of the compounds in the present disclosure or a stereoisomer or pharmaceutically acceptable salt thereof.

In one embodiment, the disease is inflammatory or autoimmune.

DETAILED DESCRIPTION OF THE DISCLOSURE Definitions

The following terms have the indicated meanings throughout the specification:

As used herein, including the appended claims, the singular forms of words such as “a,” “an,” and “the,” include their corresponding plural references unless the context clearly dictates otherwise.

The term “or” is used to mean, and is used interchangeably with, the term “and/or” unless the context clearly dictates otherwise.

The term “alkyl” refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups comprising from 1 to 18, such as from 1 to 12, further such as from 1 to 10, more further such as from 1 to 8, or from 1 to 6, or from 1 to 4, carbon atoms. Examples of alkyl groups comprising from 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl) include, but not limited to, methyl, ethyl, 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”), 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or s-butyl (“s-Bu”), 1,1-dimethylethyl or t-butyl (“t-Bu”), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl groups. The alkyl group can be optionally enriched in deuterium, e.g., —CD₃, —CD₂CD₃ and the like.

The term “halogen” refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I).

The term “haloalkyl” refers to an alkyl group in which one or more hydrogen is/are replaced by one or more halogen atoms such as fluoro, chloro, bromo, and iodo. Examples of the haloalkyl include haloC₁₋₆alkyl, haloC₁₋₆alkyl or halo C₁₋₄alkyl, but not limited to —CF₃, —CH₂Cl, —CH₂CF₃, —CCl₂, CF₃, and the like.

The term “alkyloxy” or “alkoxy” refers to an alkyl group as defined above attached to the parent molecular moiety through an oxygen atom. Examples of an alkyloxy, e.g., C₁₋₆alkyloxy or C₁₋₄ alkyloxy include, but not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy and hexoxy and the like.

The term “alkoxy-alkyl-” refers to an alkyl group as defined above further substituted with an alkoxy as defined above. Examples of an alkoxy-alkyl-, e.g., C₁₋₈alkoxy-C₁₋₈alkyl- or C₁₋₆alkoxy-C₁₋₆alkyl-include, but not limited to, methoxymethyl, ethoxymethyl, ethoxyethyl, isopropoxymethyl, or propoxymethyl and the like.

The term “amino” refers to —NH₂. The term “alkylamino” refers to —NH(alkyl). The term “dialkylamino” refers to —N(alkyl)₂.

The term “alkenyl” herein refers to a hydrocarbon group selected from linear and branched hydrocarbon groups comprising at least one C═C double bond and from 2 to 18, such as from 2 to 8, further such as from 2 to 6, carbon atoms. Examples of the alkenyl group, e.g., C2-6 alkenyl, include, but not limited to ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups.

The term “alkynyl” herein refers to a hydrocarbon group selected from linear and branched hydrocarbon group, comprising at least one C≡C triple bond and from 2 to 18, such as 2 to 8, further such as from 2 to 6, carbon atoms. Examples of the alkynyl group, e.g., C2-6 alkynyl, include, but not limited to ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

The term “cycloalkyl” refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups including fused, bridged or spiro cycloalkyl.

For example, the cycloalkyl group may comprise from 3 to 12, such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Even further for example, the cycloalkyl group may be selected from monocyclic group comprising from 3 to 12, such as from 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms. Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, Examples of the saturated monocyclic cycloalkyl group, e.g., C₃₋₆cycloalkyl, include, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embedment, the cycloalkyl is a monocyclic ring comprising 3 to 6 carbon atoms (abbreviated as C₃₋₆ cycloalkyl), including but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of the bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further Examples of the bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems.

The term “cycloalkenyl” refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple rings and having at least one double bond and preferably from 1 to 2 double bonds. In one embodiment, the cycloalkenyl is cyclopentenyl or cyclohexenyl, preferably cyclohexenyl.

The term “cycloalkynyl” refers to non-aromatic cycloalkyl groups of from 5 to 10 carbon atoms having single or multiple rings and having at least one triple bond.

The term “deuterated” is used herein to modify a chemical structure or an organic group or radical, wherein one or more carbon-bound hydrogen(s) are replaced by one or more deuterium(s), e.g., “deuterated-alkyl”, “deuterated-cycloalkyl”, “deuterated-heterocycloalkyl”, “deuterated-aryl”, “deuterated-morpholinyl”, and the like. For example, the term “deuterated-alkyl” defined above refers to an alkyl group as defined herein, wherein at least one hydrogen atom bound to carbon is replaced by a deuterium. In a deuterated alkyl group, at least one carbon atom is bound to a deuterium; and it is possible for a carbon atom to be bound to more than one deuterium; it is also possible that more than one carbon atom in the alkyl group is bound to a deuterium.

The term “aryl” used alone or in combination with other terms refers to a group selected from:

-   -   5- and 6-membered carbocyclic aromatic rings, e.g., phenyl;     -   bicyclic ring systems such as 7 to 12 membered bicyclic ring         systems, wherein at least one ring is carbocyclic and aromatic,         e.g., naphthyl and indanyl; and,     -   tricyclic ring systems such as 10 to 15 membered tricyclic ring         systems wherein at least one ring is carbocyclic and aromatic,         e.g., fluorenyl.

The terms “aromatic hydrocarbon ring” and “aryl” are used interchangeably throughout the disclosure herein. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C5-10 aryl). Examples of a monocyclic or bicyclic aromatic hydrocarbon ring include, but not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

The term “heteroaryl” herein refers to a group selected from:

-   -   5-, 6- or 7-membered aromatic, monocyclic rings comprising at         least one heteroatom, for example, from 1 to 4, or, in some         embodiments, from 1 to 3, in some embodiments, from 1 to 2,         heteroatoms, selected from nitrogen (N), sulfur (S) and oxygen         (O), with the remaining ring atoms being carbon;     -   7- to 12-membered bicyclic rings comprising at least one         heteroatom, for example, from 1 to 4, or, in some embodiments,         from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms,         selected from nitrogen, oxygen or optionally oxidized sulfur as         ring member(s), with the remaining ring atoms being carbon and         wherein at least one ring is aromatic and at least one         heteroatom is present in the aromatic ring; and     -   11- to 14-membered tricyclic rings comprising at least one         heteroatom, for example, from 1 to 4, or in some embodiments,         from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms,         selected from nitrogen, oxygen or optionally oxidized sulfur as         ring member(s), with the remaining ring atoms being carbon and         wherein at least one ring is aromatic and at least one         heteroatom is present in an aromatic ring.

When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides.

The term “optionally oxidized sulfur” used herein refers to S, SO or SO2.

The terms “aromatic heterocyclic ring” and “heteroaryl” are used interchangeably throughout the disclosure herein. In some embodiments, a monocyclic or bicyclic aromatic heterocyclic ring has 5-, 6-, 7-, 8-, 9- or 10-ring forming members with 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O) and the remaining ring members being carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a monocyclic or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a 5- to 6-membered heteroaryl ring, which is monocyclic and which has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is an 8- to 10-membered heteroaryl ring, which is bicyclic and which has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

Examples of the heteroaryl group or the monocyclic or bicyclic aromatic heterocyclic ring include, but are not limited to, (as numbered from the linkage position assigned priority 1) pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (such as 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl), tetrazolyl, thienyl (such as thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzoimidazolyl, indolyl, isoindolyl, indolinyl, oxadiazolyl (such as 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (such as 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (such as 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (such as benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl (such as furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (such as benzo[d]thiazol-6-yl), indazolyl (such as 1H-indazol-5-yl) and 5,6,7,8-tetrahydroisoquinoline.

Also, a “heteroaryl” which is further fused with a “Heterocyclyl” is defined as a “heteroaryl”.

“Heterocyclyl,” “heterocycle” or “heterocyclic” are interchangeable and refer to a non-aromatic heterocyclyl group comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro ring, i.e., containing monocyclic heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, and fused heterocyclic groups.

The term “monocyclic heterocyclyl” refers to monocyclic groups in which at least one ring member is a heteroatom selected from nitrogen, oxygen or optionally oxidized sulfur. A heterocycle may be saturated or partially saturated.

Exemplary monocyclic 4 to 9-membered heterocyclyl groups include, but not limited to, (as numbered from the linkage position assigned priority 1) pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridin-1-yl, aziridin-2-yl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, or 1,1-dioxo-thiomorpholinyl.

The term “spiro heterocyclyl” refers to a 5 to 20-membered polycyclic heterocyclyl with rings connected through one common carbon atom (called a spiro atom), comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of a spiro heterocyclyl group may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably a spiro heterocyclyl is 6 to 14-membered, and more preferably 7 to 12-membered. According to the number of common spiro atoms, a spiro heterocyclyl is divided into mono-spiro heterocyclyl, di-spiro heterocyclyl, or poly-spiro heterocyclyl, and preferably refers to mono-spiro heterocyclyl or di-spiro heterocyclyl, and more preferably 4-membered/4-membered, 3-membered/5-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro heterocyclyl.

The term “fused heterocyclic group” refers to a 5 to 20-membered polycyclic heterocyclyl group, wherein each ring in the system shares an adjacent pair of atoms (carbon and carbon atoms or carbon and nitrogen atoms) with another ring, comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of a fused heterocyclic group may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably, a fused heterocyclyl is 6 to 14-membered, and more preferably 7 to 10-membered. According to the number of membered rings, a fused heterocyclyl is divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl, preferably refers to bicyclic or tricyclic fused heterocyclyl, and more preferably 5-membered/5-membered, or 5-membered/6-membered bicyclic fused heterocyclyl. Representative examples of fused heterocycles include, but not limited to, the following groups octahydrocyclopenta[c]pyrrole (e.g., octahydrocyclopenta[c]pyrrol-2-yl), octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindolinyl (e.g., isoindoline-2-yl), octahydro-benzo[b][1,4]dioxin.

The term “bridged heterocyclyl” refers to a 5- to 14-membered polycyclic heterocyclic alkyl group, wherein every two rings in the system share two disconnected atoms, comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon. One or more rings of a bridged heterocyclyl group may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably, a bridged heterocyclyl is 6 to 14-membered, and more preferably 7 to 10-membered. According to the number of membered rings, a bridged heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and preferably refers to bicyclic, tricyclic or tetracyclic bridged heterocyclyl, and more preferably bicyclic or tricyclic bridged heterocyclyl. Representative examples of bridged heterocyclyls include, but not limited to, the following groups: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[3.3.2]decyl.

Compounds disclosed herein may contain an asymmetric center and may thus exist as enantiomers. “Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. Where the compounds disclosed herein possess two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers are intended to be included. All stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.

The term “substantially pure” as used herein means that the target stereoisomer contains no more than 35%, such as no more than 30%, further such as no more than 25%, even further such as no more than 20%, by weight of any other stereoisomer(s). In some embodiments, the term “substantially pure” means that the target stereoisomer contains no more than 10%, for example, no more than 5%, such as no more than 1%, by weight of any other stereoisomer(s).

When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are meant to include both E and Z geometric isomers.

When compounds disclosed herein contain a di-substituted cyclohexyl or cyclobutyl group, substituents found on cyclohexyl or cyclobutyl ring may adopt cis and trans formations. Cis formation means that both substituents are found on the upper side of the 2 substituent placements on the carbon, while trans would mean that they were on opposing sides.

It may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (“SMB”) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography. One skilled in the art will apply techniques most likely to achieve the desired separation.

“Diastereomers” refers to stereoisomers of a compound with two or more chiral centers but which are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.

A single stereoisomer, e.g., a substantially pure enantiomer, may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents [Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller C. H., et al. “Chromatographic resolution of enantiomers: Selective review.” J Chromatogr., 113 (3) (1975): pp. 283-302]. Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer Irving W, Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker Inc., 1993.

“Pharmaceutically acceptable salts” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base function with a suitable organic acid or by reacting the acidic group with a suitable base.

In addition, if a compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

As defined herein, “a pharmaceutically acceptable salt thereof” include salts of at least one compound of Formula (I), and salts of the stereoisomers of the compound of Formula (I), such as salts of enantiomers, and/or salts of diastereomers.

The terms “administration”, “administering”, “treating” and “treatment” herein, when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, mean contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell. The term “administration” and “treatment” also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell. The term “subject” herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit) and most preferably a human.

The term “effective amount” or “therapeutically effective amount” refers to an amount of the active ingredient, such as compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. The “therapeutically effective amount” can vary with the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments. In some embodiments, “therapeutically effective amount” is an amount of at least one compound and/or at least one stereoisomer thereof, and/or at least one pharmaceutically acceptable salt thereof disclosed herein effective to “treat” as defined above, a disease or disorder in a subject. In the case of combination therapy, the “therapeutically effective amount” refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.

The pharmaceutical composition comprising the compound disclosed herein can be administrated via oral, inhalation, rectal, parenteral or topical administration to a subject in need thereof. For oral administration, the pharmaceutical composition may be a regular solid Formulation such as tablets, powder, granule, capsules and the like, a liquid Formulation such as water or oil suspension or other liquid Formulation such as syrup, solution, suspension or the like; for parenteral administration, the pharmaceutical composition may be solution, water solution, oil suspension concentrate, lyophilized powder or the like. Preferably, the Formulation of the pharmaceutical composition is selected from tablet, coated tablet, capsule, suppository, nasal spray or injection, more preferably tablet or capsule. The pharmaceutical composition can be a single unit administration with an accurate dosage. In addition, the pharmaceutical composition may further comprise additional active ingredients.

All Formulations of the pharmaceutical composition disclosed herein can be produced by the conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients, then to make the desired Formulation. The “pharmaceutically acceptable excipient” refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical Formulation, for example: a diluent, a vehicle such as water, various organic solvents, etc., a filler such as starch, sucrose, etc. a binder such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone (PVP); a wetting agent such as glycerol; a disintegrating agent such as agar, calcium carbonate and sodium bicarbonate; an absorption enhancer such as quaternary ammonium compound; a surfactant such as hexadecanol; an absorption carrier such as Kaolin and soap clay; a lubricant such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition further comprises other pharmaceutically acceptable excipients such as a decentralized agent, a stabilizer, a thickener, a complexing agent, a buffering agent, a permeation enhancer, a polymer, aromatics, a sweetener, and a dye.

The term “disease” refers to any disease, discomfort, illness, symptoms or indications, and can be interchangeable with the term “disorder” or “condition”.

Throughout this specification and the claims which follow, unless the context requires otherwise, the term “comprise,” and variations such as “comprises” and “comprising” are intended to specify the presence of the features thereafter, but do not exclude the presence or addition of one or more other features. When used herein the term “comprising” can be substituted with the term “containing”, “including” or sometimes “having”.

Throughout this specification and the claims which follow, the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-8, C1-6, and the like.

Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

Example

The examples below are intended to be purely exemplary and should not be considered to be limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (for example, amounts, temperature, etc.), but some experimental errors and deviations should be accounted for. Unless indicated otherwise, temperature is in degrees Centigrade. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, AlfaAesar, or TCI, and were used without further purification unless indicated otherwise.

Unless indicated otherwise, the reactions set forth below were performed under a positive pressure of nitrogen or argon or with a drying tube in anhydrous solvents; the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe; and glassware was oven dried and/or heat dried.

Unless otherwise indicated, the reactions set forth below were performed under a positive pressure of nitrogen or argon or with a drying tube in anhydrous solvents; the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe; and glassware was oven dried and/or heat dried.

Unless otherwise indicated, column chromatography purification was conducted on a Biotage system (Manufacturer: Dyax Corporation) having a silica gel column or on a silica SepPak cartridge (Waters), or was conducted on a Teledyne Isco Combiflash purification system using prepacked silica gel cartridges.

¹H NMR spectra were recorded on a Varian instrument operating at 400 MHz. ¹H NMR spectra were obtained using CDCl₃, CD₂Cl₂, CD₃OD, D₂O, d₆-DMSO, d₆-acetone or (CD₃)₂CO as solvent and tetramethylsilane (0.00 ppm) or residual solvent (CDCl₃: 7.25 ppm; CD₃OD: 3.31 ppm; D₂O: 4.79 ppm; d₆-DMSO: 2.50 ppm; d₆-acetone: 2.05; (CD₃)₂CO: 2.05) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintuplet), sx (sextuplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz). Compound names except the reagents were generated by ChemDraw version 12.0.

Abbreviations

-   -   AcOH Acetic acid     -   Aq Aqueous     -   Brine Saturated aqueous sodium chloride solution     -   Bn Benzyl     -   BnBr Benzyl Bromide     -   (Boc)₂O di-tert-butyl dicarbonate     -   DMF N,N-Dimethylformamide     -   Dppf 1,1″-bis(diphenylphosphino)ferrocene     -   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene     -   DIEA or DIPEA N-ethyl-N-isopropylpropan-2-amine     -   DMAP 4-N,N-dimethylaminopyridine     -   DMSO Dimethyl sulfoxide     -   EtOAc or EA EA     -   EtOH Ethanol     -   Et₂O or ether Diethyl ether     -   Et₃N Triethyl amine     -   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium         hexafluorophosphate     -   HPLC High-performance liquid chromatography     -   IPA 2-propanol     -   i-PrOH Isopropyl alcohol     -   ms or MS Mass spectrum     -   NaHMDS Sodium Hexamethylenedisilazane     -   PE petroleum ether     -   PPA Polyphosphoric acid     -   p-TSA p-Tolunesulfonic acid     -   Rt Retention time     -   Rt or rt Room temperature     -   TBAF Tetra-butyl ammonium fluoride     -   TBSCl tert-Butyldimethylsilyl chloride     -   TFA Trifluoroacetic acid     -   THF tetrahydrofuran     -   TLC thin layer chromatography

Example BB1: Synthesis of 2-bromo-4-(methoxymethyl)-6-(methylsulfonyl)pyridine

Step 1: 2,6-dibromo-4-(bromomethyl)pyridine

A mixture of 2,6-dibromo-4-methylpyridine (10.0 g, 39.85 mmol), CCl₄ (100 mL), AIBN (1.31 g, 7.98 mmol) and NBS (10.64 g, 59.78 mmol) was stirred for 15 h at 80° C. After cooled to room temperature, DCM (100 mL) was added and the resulting mixture was washed with H₂O (150 mL×3). The mixture was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-20%) give 2,6-dibromo-4-(bromomethyl)pyridine (10.0 g, 76%). LCMS (ESI) m/e [M+1]⁺ 328.

Step 2: 2,6-dibromo-4-(methoxymethyl)pyridine

A mixture of 2,6-dibromo-4-(bromomethyl)pyridine (10.0 g, 30.32 mmol), MeOH (100 mL) and K₂CO₃ (8.38 g, 60.63 mmol) was stirred for 2 h at RT. Upon completion of the reaction, EA (200 mL) was added and the resulting mixture was washed with H₂O (200 mL×3). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-25%) to give 2,6-dibromo-4-(methoxymethyl)pyridine (2.00 g, 23%). LCMS (ESI) m/e [M+1]⁺ 280.

Step 3: 2-bromo-4-(methoxymethyl)-6-(methylsulfanyl)pyridine

A mixture of 2,6-dibromo-4-(methoxymethyl)pyridine (2.00 g, 7.12 mmol), DMF (20 mL) and NaSCH₃ (0.50 g, 7.14 mmol) was stirred for 1 h at RT. Upon completion of the reaction, EA (100 mL) was added and the resulting mixture was washed with H₂O (200 mL×3). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-25%) to give 2-bromo-4-(methoxymethyl)-6-(methylsulfanyl)pyridine (1.40 g, 79%). LCMS (ESI) m/e [M+1]⁺ 248.

Step 4: 2-bromo-6-methanesulfonyl-4-(methoxymethyl)pyridine

A mixture of 2-bromo-4-(methoxymethyl)-6-(methylsulfanyl)pyridine (1.40 g, 5.64 mmol), THE (10 mL), H₂O (10.00 mL), NaIO₄ (2.41 g, 11.26 mmol) and RuCl₃·H₂O (127.19 mg, 0.56 mmol) was stirred for 1 h at 0° C. Upon completion of the reaction, EA (100 mL) was added and the resulting mixture was washed with H₂O (200 mL×3). The organic layer was dried over anhydrous Na₂SO₄, concentrated and purified by combi-flash (EA/PE=0-30%) give 2-bromo-6-methanesulfonyl-4-(methoxymethyl)pyridine (1.10 g, 69%). ¹H NMR (300 MHz, CDCl₃) δ 7.99 (s, 1H), 7.74 (s, 1H), 4.56 (s, 2H), 3.50 (s, 3H), 3.27 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 280.

Example BB2: Synthesis of 2-bromo-4-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]-6-methanesulfonyl pyridine

Step 1: 2-bromo-6-(methylthio)pyridin-4-ol

A mixture of 2, 6-dibromopyridin-4-ol (10.00 g, 39.542 mmol), DIEA (10.22 g, 0.079 mmol), Xantphos (0.23 g, 0.39 mmol), NaSCH₃ (2.93 g, 39.54 mmol) and Pd₂(dba)₃ (0.18 g, 0.20 mmol) in 1,4-dioxane (200 mL) was stirred overnight at 75° C. under nitrogen atmosphere. After cooled to room temperature, water was added and the resulting mixture was extracted with EA (100 mL×3). The combined organic layers were washed with water, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum and the crude product 2-bromo-6-(methylthio)pyridin-4-ol was used directly for next step without further purification. LCMS (ESI) m/e [M+1]⁺ 220.

Step 2: 2-bromo-6-methanesulfonylpyridin-4-ol

To a stirred solution of 2-bromo-6-(methylsulfanyl)pyridin-4-ol (6.00 g, 27.26 mmol) in H₂O (100 mL)/THF (100 mL) was added RuCl₃·H₂O (0.18 g, 0.82 mmol) in water (30 mL) dropwise at 0° C., then NaIO₄ (11.66 g, 0.055 mmol) was added dropwise successively at 0° C. The resulting mixture was stirred for additional 30 mins at 0° C. Upon completion of the reaction, the resulting mixture was extracted with EA (100 mL×3). The combined organic layers were washed with water, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM/MeOH=12:1) to give 2-bromo-6-methanesulfonylpyridin-4-ol (3 g, 44%). LCMS (ESI) m/e [M+1]⁺ 252.

Step 3: 2-bromo-4-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]-6-methanesulfonylpyridine

A mixture of 2-bromo-6-methanesulfonylpyridin-4-ol (1.00 g, 3.97 mmol), K₂CO₃ (1.10 g, 79.59 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (1.90 g, 79.42 mmol) in DMF (20 mL) was stirred for 3 h at 60° C. After cooled to room temperature, water was added and the resulting mixture was extracted with EA (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by Prep-TLC (hexane/EA=5:1) to give the product (1.08 g, 68%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.62 (s 1H), 7.54 (s 1H), 4.30-4.25 (m, 2H), 3.90-3.87 (m, 2H), 3.28 (s, 3H), 0.85 (s, 9H), 0.06 (s, 6H). LCMS (ESI) m/e [M+1]⁺ 410.

Example BB3: Synthesis of 2-bromo-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-6-(methyl sulfonyl)pyridine

A mixture of 2-bromo-6-methanesulfonylpyridin-4-ol (200 mg, 0.79 mmol), Cs₂CO₃ (517.01 mg, 1.59 mmol) and (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (272.62 mg, 0.95 mmol) in DMF (5 mL) was stirred for 3 h at 80° C. under nitrogen atmosphere. After cool to room temperature, water was added and the resulting mixture was extracted with EA (100 mL×3). The combined organic layers were washed with water, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by Prep-TLC (PE/EA=5:1) to give 2-bromo-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-6-(methylsulfonyl)pyridine (260 mg, 89%). ¹H NMR (300 MHz, MeOD-d₄) δ 7.64 (s, 1H), 7.49 (s, 1H), 4.59-4.40 (m, 1H), 4.32-4.13 (m, 3H), 3.89 (d, J=8.6 Hz, 1H), 3.23 (s, 3H), 1.41 (s, 3H), 1.37 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 366.

Example BB4: Synthesis of 2-bromo-4-(2-((tert-butyldimethylsilyl)oxy)propoxy)-6-(methylsulfonyl)pyridine

Step 1: 1-((2-Bromo-6-(methylsulfonyl)pyridin-4-yl)oxy)propan-2-ol

A mixture of 2-bromo-6-methanesulfonylpyridin-4-ol (500 mg, 1.98 mmol), 2-propanol-1-bromo (4.14 g, 29.75 mmol) and K₂CO₃ (548 mg, 3.97 mmol) in DMF (5 mL) was stirred for 12 h at 70° C. After cool to room temperature, water was added and the resulting mixture was extracted with EA (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated to give the crude product 1-((2-Bromo-6-(methylsulfonyl)pyridin-4-yl)oxy)propan-2-ol was used for the next step directly without further purification. LCMS (ESI) m/e [M+1]⁺ 310.

Step 2: 2-Bromo-4-(2-((tert-butyldimethylsilyl)oxy)propoxy)-6-(methylsulfonyl)pyridine

A solution of 1-[(2-bromo-6-methanesulfonylpyridin-4-yl)oxy]propan-2-ol (600 mg, 1.93 mmol), TBSCl (437.4 mg, 2.90 mmol) and DIEA (500 mg, 3.87 mmol) in DCM (10 mL) was stirred for 12 h at RT. Upon completion of the reaction, the solvent was removed and the residue was purified by Prep-TLC (EA/PE=1:3) to give 2-bromo-4-[2-[(tert-butyldimethylsilyl)oxy]propoxy]-6-methanesulfonylpyridine (635 mg, 77%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.61 (s, 1H), 7.52 (s, 1H), 4.24-4.05 (m, 1H), 3.35 (s, 3H), 3.28 (d, J=4.4 Hz, 2H), 1.25-1.20 (m, 3H), 0.82 (s, 9H), 0.08 (s, 6H). LCMS (ESI) m/e [M+1]⁺ 425.

Example 1B1B5: Synthesis of 2-[(2-bromo-6-methanesulfonylpyridin-4-yl)oxy]acetonitrile

To a stirred solution of 2-bromo-6-methanesulfonylpyridin-4-ol (500 mg, 1.98 mmol) and 2-bromoacetonitrile (475 mg, 3.97 mmol) in DMF (10 mL) was added K₂CO₃ (548 mg, 3.97 mmol) in portions at room temperature, then the resulting mixture was stirred overnight at 80° C. After cooled to room temperature, water was added and the resulting mixture was extracted with EA (40 mL×3). The combined organic layers were washed with brine (3×30 mL), dried over anhydrous Na₂SO₄, concentrated and purified by Prep-TLC (PE/EA=3:1) to give 2-[(2-bromo-6-methanesulfonylpyridin-4-yl)oxy]acetonitrile (254.3 mg, 44%). ¹H NMR (300 MHz, MeOD-d₄) δ 7.73 (s, 1H), 7.63 (s, 1H), 5.27 (s, 2H), 3.27 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 291.

Example BB6: Synthesis of 2-bromo-4-isopropoxy-6-methanesulfonylpyridine

To a stirred solution of 2-bromo-6-methanesulfonylpyridin-4-ol (600 mg, 2.38 mmol) and 2-iodopropane (809 mg, 4.76 mmol) in DMF (10 mL) was added K₂CO₃ (658 mg, 4.76 mmol) in portions at room temperature. After cooled to room temperature, water was added and the resulting mixture was extracted with EA (40 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by Prep-TLC (PE/EA=3:1) to give the product (570 mg, 82%). ¹H NMR (400 MHz, MeOD-d₄) δ 7.54 (s, 1H), 7.41 (s, 1H), 4.96-4.85 (m, 1H), 3.24 (s, 3H), 1.40 (d, J=6.1 Hz, 6H). LCMS (ESI) m/e [M+1]⁺ 294.

Example BB7: Synthesis of 2-bromo-6-methanesulfonyl-4-[(trans)-3-[(tert-butyldimethylsilyl)oxy]cyclobutoxy]pyridine

A solution of 2-bromo-6-methanesulfonylpyridin-4-ol (2.00 g, 7.93 mmol), PPh₃ (3.12 g, 11.89 mmol), DIAD (2.41 g, 11.92 mmol) and trans-3-[(tert-butyldimethylsilyl)oxy]cyclobutan-1-ol (1.61 g, 7.95 mmol) in THF (100 mL) was stirred overnight at 50° C. After cooled to room temperature, water was added and the resulting mixture was extracted with EA (40 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by Prep-TLC (hexane/EA=5:1) to give the product (2.06 g, 60%). ¹H NMR (300 MHz, MeOD-d₄) δ 7.48 (s, 1H), 7.29 (s, 1H), 5.03 (t, J=6.3 Hz, 1H), 4.70-4.52 (m, 1H), 3.23 (s, 3H), 2.59-2.37 (m, 4H), 0.92 (s, 9H), 0.08 (s, 6H). LCMS (ESI) m/e [M+1]⁺ 436.

Example BB8: Synthesis of 2-bromo-6-methanesulfonylpyridine-4-carbonitrile

Step 1: 2-bromo-6-(methylsulfanyl)pyridine-4-carbonitrile

A mixture of 2,6-dibromopyridine-4-carbonitrile (4.00 g, 15.27 mmol), DMF (40 mL) and CH₃SNa (1.28 g, 18.33 mmol) was stirred overnight at rt. Upon completion of the reaction, water was added and the resulting solution was extracted with EA (60 mL×3). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄. The solid were filtered out and the resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-5%) to give the product (1.50 g, 43%). GCMS (ESI) [M] 228.

Step 2: 2-bromo-6-methanesulfonylpyridine-4-carbonitrile

To a solution of 2-bromo-6-(methylsulfanyl)pyridine-4-carbonitrile (1.50 g, 6.55 mmol) in THF (15 mL) was added NaIO₄ (2.80 g, 13.10 mmol) in H₂O (20 mL) in portions at 0° C., then to this was added RuCl₃·H₂O (147.60 mg, 0.655 mmol) in H₂O (10 mL) in portions at 0° C. The resulting solution was stirred for 2 h at RT. Upon completion of the reaction, the resulting solution was extracted with EA (60 mL×3) and the combined organic layer was washed with brine, dried over anhydrous Na₂SO₄. The solid was filtered out and the resulting mixture was concentrated under vacuum and the residue was purified by Prep-TLC (EA/PE=1:2) to give the product (1.06 g, 62%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.65 (s, 1H), 8.55 (s, 1H), 3.40 (s, 3H); GC-MS (ESI) [M] 260.

Example BB9: Synthesis of 2-bromo-6-methanesulfonyl-4-methoxypyridine

To a mixture of 2-bromo-6-methanesulfonylpyridin-4-ol (5.00 g, 19.84 mmol) and K₂CO₃ (5.49 g, 0.04 mmol) in DMF (100 mL) was added CH₃I (4.20 g, 29.59 mmol) dropwise at 60° C. for 2 h. After cooled to rt, water was added and the resulting mixture was extracted with EA (150 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by combi-flash (EA/PE=25-35%) to give the product (4.00 g, 76%). ¹H NMR (300 MHz, CDCl₃) δ 7.56 (s, 1H), 7.18 (s, 1H), 3.95 (s, 3H), 3.24 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 266.

Example BB10: Synthesis of 6-bromo-4-methylpyridine-2-sulfonamide

Step 1: 2-(benzylsulfanyl)-6-bromo-4-methylpyridine

A mixture of 2,6-dibromo-4-methylpyridine (2.00 g, 7.97 mmol), DMF (30 mL), benzyl mercaptan (1.09 g, 8.78 mmol) and Cs₂CO₃ (5.19 g, 15.93 mmol) was stirred for 2 h at RT. Upon completion of the reaction, EA (100 mL) was added and the resulting mixture was washed with water (100 mL×3). Then the mixture was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-25%) give the product (2.30 g, 98%). LCMS (ESI) m/e [M+1]⁺ 294.

Step 2: 6-bromo-4-methylpyridine-2-sulfonyl chloride

A mixture of 2-(benzylsulfanyl)-6-bromo-4-methylpyridine (2.30 g, 7.82 mmol), AcOH (36 mL), H₂O (4 mL) and NCS (3.65 g, 27.33 mmol) was stirred for 1 h at RT. Upon completion of the reaction, EA (100 mL) was added and the resulting mixture was washed with water (100 mL×3). The mixture was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-25%) give the product (2.00 g, 94%).

Step 3: 4-methylpyridine-2-sulfonamide

A solution of 6-bromo-4-methylpyridine-2-sulfonyl chloride (2.00 g, 7.39 mmol) in THF (20 mL) was added ammonium (10 mL, 33% wt) dropwise at 0° C. and was stirred for 1 h at RT. Upon completion of the reaction, EA (100 mL) was added and the resulting mixture was washed with water (100 mL×3). The mixture was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by combi-flash (EA/PE=0-50%) give the product (1.02 g, 55%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.84 (s, 1H), 7.62 (s, 2H), 7.37 (s, 1H), 2.43 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 251.

Example BB11: Synthesis of 6-bromo-4-(2-methoxyethoxy)pyridine-2-sulfonamide

Step 1: 2,6-dibromo-4-(2-methoxyethoxy)pyridine

A mixture of 2, 6-dibromopyridin-4-ol (2.02 g, 7.90 mmol), 2-bromoethyl methyl ether (1.65 g, 11.86 mmol) and K₂CO₃ (2.19 g, 15.82 mmol) in DMF (10.00 mL) was stirred at 80° C. for 3 h. After cooled to RT, water was added and the resulting mixture was extracted with EA (150 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum to afford crude product. The crude product was used for the next step directly without further purification. LCMS (ESI) m/e [M+1]⁺ 310.

Step 2: 6-bromo-4-(2-methoxyethoxy)pyridine-2-sulfonyl chloride

To a stirred solution of 2,6-dibromo-4-(2-methoxyethoxy)pyridine (1.90 g, 6.11 mmol) in THF (10 mL) was added i-PrMgCl (4.0 mL, 8.00 mmol, 2M) dropwise at 0° C. and the resulting mixture was stirred for 1 h at RT. under nitrogen atmosphere. SO₂Cl₂ (1.2 mL) in hexane (3 mL) was added dropwise at 0° C. and the resulting mixture was stirred for 1 h at rt under nitrogen atmosphere. Upon completion of the reaction, the reaction was quenched with cool water. The resulting mixture was concentrated under vacuum to afford crude product 6-bromo-4-(2-methoxyethoxy) pyridine-2-sulfonyl chloride (2.0 g). It was used directly for next step without purification.

Step 3: 6-bromo-4-(2-methoxyethoxy)pyridine-2-sulfonamide

A mixture of 6-bromo-4-(2-methoxyethoxy) pyridine-2-sulfonyl chloride (1.80 g, 5.44 mmol) in NH₃/THF (0.5M, 33 mL) was stirred at 1 h at RT. Upon completion of the reaction, the solvent was removed under vacuum and the residue was purified by prep-HPLC (column: Phenomenex Gemini-NX; phase: A-H₂O; B-Acetonitrile, B %: 15%-25% in 15 min) to give the product (128 mg, 81%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.63 (s, 2H), 7.52 (s, 1H), 7.43 (s, 1H), 4.34-4.32 (m, 2H), 3.68-3.66 (m, 2H), 3.31 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 312.

Example BB12: Synthesis of 2-bromo-4-(difluoromethyl)-6-(methylsulfonyl)pyridine

Step 1: (2,6-dibromopyridin-4-yl)methanol

A solution of 2,6-dibromopyridine-4-carboxylic acid (2.00 g, 7.12 mmol) in THF (20 mL) was added BH₃·THF (14 mL, 14.00 mmol, 1 M in THF) dropwise and the resulting mixture was stirred for 48 h at RT. Upon completion of the reaction, water was added slowly to quench the reaction and the resulting mixture was extracted with EA (3×200 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The crude product was used directly for the next step without further purification. LCMS (ESI) m/e [M+1]⁺ 266.

Step 2: 2,6-dibromoisonicotinaldehyde

A solution of (2, 6-dibromopyridin-4-yl)methanol (1.50 g, 5.62 mmol) and DMP (3.58 g, 8.43 mmol) in DCM (15 mL) was stirred for 12 h at RT. Upon completion of the reaction, water was added and the resulting mixture was extracted with DCM (200 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by Prep-TLC (DCM/PE=1:1) to give the product (900 mg, 60%).

Step 3: 2,6-dibromo-4-(difluoromethyl)pyridine

To a stirred solution of 2,6-dibromopyridine-4-carbaldehyde (850 mg, 3.21 mmol) in DCM (8.5 mL) was added DAST (1.55 g, 9.63 mmol) dropwise at rt. The resulting mixture was stirred for additional 1 h at RT. Upon completion of the reaction, EtOH was added and the resulting mixture was concentrated under vacuum. The crude product was used directly for the next step without further purification. LCMS (ESI) m/e [M+1]⁺ 286.

Step 4: 2-bromo-4-(difluoromethyl)-6-(methylthio)pyridine

A solution of 2,6-dibromo-4-(difluoromethyl)pyridine (1.00 g, 3.49 mmol) and MeSNa (195 mg, 2.79 mmol) in DMF (10 mL) was stirred for 2 h at RT. Upon completion of the reaction, water was added and the resulting mixture was extracted with EA (100 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The crude product was used directly for the next step without further purification. LCMS (ESI) m/e [M+1]⁺ 254.

Step 5: 2-bromo-4-(difluoromethyl)-6-(methylsulfonyl)pyridine

To a stirred solution of 2-bromo-4-(difluoromethyl)-6-(methylsulfanyl)pyridine (450 mg, 1.77 mmol) in H₂O (5 mL) and THF (5 mL) was added RuCl₃·H₂O (12 mg, 0.053 mmol) in water (2 mL) dropwise at 0° C. To the above mixture was added NaIO₄ (1515 mg, 7.08 mmol) dropwise at 0° C. The resulting mixture was stirred for additional 30 mins at 0° C. Upon completion of the reaction, the resulting mixture was extracted with EA (3×100 mL) and the combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by Prep-TLC (EA/PE=1:4) to give the product (317 mg, 63%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.28 (s, 1H), 8.21 (s, 1H), 7.40-7.05 (m, 1H), 3.37 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 286.

Example BB13: Synthesis of 2-bromo-6-methanesulfonyl-4-(oxetan-3-ylmethoxy) pyridine

A mixture of 2-bromo-6-methanesulfonylpyridin-4-ol (1.00 g, 3.97 mmol), PPh₃ (3.12 g, 11.89 mmol), DIAD (2.41 g, 11.92 mmol) and oxetan-3-ylmethanol (0.35 g, 3.97 mmol) in THF (20 mL) was stirred overnight at 50° C. After cooled to RT, water was added and the resulting mixture was extracted with EA (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by Prep-TLC (hexane/EA=5:1) to give the product (996 mg, 78%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.65 (s, 1H), 7.58 (s, 1H), 4.71 (d, J=7.9 Hz, 2H), 4.52-4.37 (m, 4H), 3.49-3.37 (m, 1H), 2.54 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 322.

Example BB14: Synthesis of 2-bromo-6-methanesulfonyl-4-(oxetan-3-yloxy) pyridine

A solution of 2-bromo-6-methanesulfonylpyridin-4-ol (826 mg, 3.27 mmol), PPh₃ (3.12 g, 11.89 mmol), DIAD (2.41 g, 11.92 mmol)) and oxetan-3-ol (0.59 g, 7.93 mmol) in THF (20 mL) was stirred overnight at 50° C. After cooled to RT, water was added, and the resulting mixture was extracted with EA (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by Prep-TLC (hexane/EA=5:1) to give (899 mg, 89%) of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 7.50 (s, 1H), 7.45 (s, 1H), 5.59-5.50 (m, 1H), 4.99-4.95 (m, 2H), 4.60-4.55 (m, 2H), 3.29 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 308.

Example BB15: Synthesis of 2-bromo-6-methanesulfonyl-4-(oxetan-3-ylmethoxy) pyridine

A solution of 2-bromo-6-methanesulfonylpyridin-4-ol (1.00 g, 3.97 mmol), PPh₃ (3.12 g, 11.89 mmol), DIAD (2.41 g, 11.92 mmol) and 2-methoxypropan-1-ol (0.44 g, 3.97 mmol) in THF (20 mL) was stirred overnight at 50° C. After cooled to RT, water was added and the resulting mixture was extracted with EA (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by Prep-TLC (hexane/EA=5:1) to give the product (900 mg, 70%) of the product. ¹H NMR (300 MHz, DMSO-d₆) δ 7.63 (s, 1H), 7.56 (s, 1H), 4.31-4.14 (m, 2H), 3.70-3.65 (m, 1H), 3.39 (m, 3H), 3.25 (m, 3H), 1.17-1.14 (m, 3H). LCMS (ESI) m/e [M+1]⁺ 324.

Example BB16: Synthesis of 2-bromo-6-methanesulfonyl-3-methoxypyridine

Step 1: 2-bromo-3-methoxy-6-(methylsulfanyl)pyridine

A mixture of 2-bromo-6-iodo-3-methoxypyridine (4.00 g, 12.74 mmol), (methylsulfanyl)sodium (0.80 g, 11.41 mmol), Pd₂(dba)₃ (0.58 g, 0.63 mmol), Xantphos (0.74 g, 1.27 mmol) in dioxane (64 mL) was stirred for 3 h at 75° C. under nitrogen atmosphere. After cooled to rt, water was added, and the resulting mixture was extracted with EA (200 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum and purified by combi-flash (EA/PE=0-4%) to give the product (1.72 g, 52%). LCMS (ESI, m/e) [M+1]⁺ 234.

Step 2: 2-bromo-6-methanesulfonyl-3-methoxypyridine

To a mixture of 2-bromo-3-methoxy-6-(methylsulfanyl)pyridine (1.72 g, 7.34 mmol) in THF (15 mL) were added NaIO4 (4.73 g, 22.14 mmol) and RuCl₃ (0.05 g, 0.22 mmol) in H₂O (15 mL) dropwise at 0° C. The resulting solution was stirred for 1 h at RT. Upon completion of the reaction, the resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-39%) to give the product (1.78 g, 82%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.06 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 4.01 (s, 3H), 3.24 (s, 3H). LCMS (ESI, m/e) [M+1]⁺ 266.

Example BB17: Synthesis of 1-bromo-3-methanesulfonyl-5-(2-methoxyethoxy) benzene

Step 1: 1,3-dibromo-5-(2-methoxyethoxy) benzene

A mixture of 3,5-dibromophenol (11.00 g, 43.66 mmol), 2-bromoethyl methyl ether (15.17 g, 109.14 mmol) and Cs₂CO₃ (28.46 g, 87.33 mmol) in DMF (165 mL) was stirred for 4 h at 80° C. After cooled to RT, water was added then extracted with EA (500 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated to give the crude product and used directly for the next step without further purification. LCMS (ESI, m/e) [M+1]⁺ 311.

Step 2: 1-bromo-3-(2-methoxyethoxy)-5-(methylsulfanyl) benzene

A mixture of 1,3-dibromo-5-(2-methoxyethoxy) benzene (15.00 g, 48.39 mmol), (methylsulfanyl)sodium (2.71 g, 38.67 mmol), Pd₂(dba)₃ (2.22 g, 2.42 mmol), Xantphos (2.80 g, 4.83 mmol) in dioxane (150 mL) was stirred overnight at 75° C. under nitrogen atmosphere. After cooled to RT, the resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-1%) to give the product (5.71 g, 38%). LCMS (ESI, m/e) [M+1]⁺ 277.

Step 3: 1-bromo-3-methanesulfonyl-5-(2-methoxyethoxy) benzene

To a mixture of 1-bromo-3-(2-methoxyethoxy)-5-(methylsulfanyl) benzene (5.71 g, 20.60 mmol) in THF (60 mL) and H₂O (30 mL) was added the solution of NaIO₄ (13.22 g, 61.81 mmol) in H₂O (15 mL) in portions at 0° C. Then to the mixture was added the solution of RuCl₃ (0.14 g, 0.62 mmol) in H₂O (15 mL) in portions at 0° C. The resulting solution was stirred for 1 h at RT. Upon completion of the reaction, the resulting solution was extracted with EA (50 mL×3). The solvent was removed under vacuum and the residue was purified by combi-flash (EA/PE=0-31%) to give the product (4.99 g, 71%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.65 (s, 1H), 7.56 (s, 1H), 7.46 (s, 1H), 4.30-4.22 (m, 2H), 3.70-3.65 (m, 2H), 3.31 (s, 3H), 3.29 (s, 3H). LCMS (ESI, m/e) [M+1]⁺ 309.

Example BB18: Synthesis of [2-(3-bromo-5-methanesulfonylphenoxy)ethoxy](tert-butyl)dimethylsilane

Step 1: tert-butyl[2-(3,5-dibromophenoxy)ethoxy]dimethylsilane

A mixture of 3,5-dibromophenol (5.00 g, 19.85 mmol), (2-bromoethoxy)(tert-butyl)dimethyl silane (7.12 g, 29.77 mmol), Cs₂CO₃ (12.93 g, 39.69 mmol) in DMF (50 mL) was stirred for 2 h at 80° C. After cooled to RT, water was added and the resulting mixture was extracted with EA (80 mL×3). The combined organic layers were washed with water, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-20%) to give the product (5.00 g, 61%).

Step 2: [2-[3-bromo-5-(methylsulfanyl)phenoxy]ethoxy](tert-butyl)dimethylsilane

A mixture of tert-butyl[2-(3,5-dibromophenoxy)ethoxy]dimethylsilane (5.00 g, 12.19 mmol), (methylsulfanyl)sodium (768 mg, 10.97 mmol), Xantphos (705 mg, 1.22 mmol), DIEA (3.15 g, 24.38 mmol), Pd₂(dba)₃ (558 mg, 0.61 mmol) and 1,4-dioxane (50 mL) was stirred overnight at 90° C. under nitrogen atmosphere. After cooled to RT, water was added, and the resulting mixture was extracted with EA (120 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-10%) to give the product (2.80 g, 60%). LCMS (ESI, m/e) [M+1]⁺ 377.

Step 3: [2-(3-bromo-5-methanesulfonylphenoxy)ethoxy](tert-butyl)dimethylsilane

To a stirred solution of [2-[3-bromo-5-(methylsulfanyl)phenoxy]ethoxy](tert-butyl)dimethylsilane (2.80 g, 7.41 mmol) in THF (30 mL) were added RuCl₃·H₂O (50 mg, 0.22 mmol) and NaIO₄ (3.17 g, 14.84 mmol) in H₂O (20 mL) at 0° C. and the resulting solution was stirred for 2 h at this temperature. Upon completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-30%) to give the product (1.07 g, 35%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.64 (s, 1H), 7.57-7.52 (m, 1H), 7.44 (s, 1H), 4.20-4.15 (m, 2H), 3.96-3.90 (m, 2H), 3.29 (s, 3H), 0.86 (s, 9H), 0.07 (s, 6H). LCMS (ESI) m/e [M+1]⁺ 409.

Example BB19: Synthesis of 1-bromo-3-isopropoxy-5-(methylsulfonyl)benzene Step 1: 1,3-dibromo-5-isopropoxybenzene

A mixture of 3,5-dibromophenol (10 g, 39.69 mmol), DMF (200 mL), 2-iodopropane (20.24 g, 119.06 mmol) and K₂CO₃ (10.97 g, 79.38 mmol) was stirred for 2 h at 80° C. After cooled to RT, EA (200 mL) was added and the resulting mixture was washed with H₂O (200 mL×3). The mixture was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-15%) give the product (7.6 g, 65%).

Step 2: 1-bromo-3-isopropoxy-5-(methylsulfanyl)benzene

A mixture of 1,3-dibromo-5-isopropoxybenzene (7.60 g, 25.85 mmol), dioxane (100 mL), Pd₂(dba)₃ (1.18 g, 1.29 mmol), Xantphos (1.50 g, 2.59 mmol), MeSNa (1.81 g, 25.85 mmol) was stirred for 3 h at 75° C. After cooled to RT, EA (200 mL) was added and the resulting mixture was washed with H₂O (200 mL×3). The mixture was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-15%) give the product (7.1 g, crude). GCMS (ESI) m/e [M+1]260.

Step 3: 1-bromo-3-isopropoxy-5-(methylsulfonyl)benzene

A mixture of 1-bromo-3-isopropoxy-5-(methylsulfanyl)benzene (7.10 g, 27.18 mmol), THF (60 mL), H₂O (60 mL), NaIO₄ (23.26 g, 108.75 mmol) and RuCl₃·H₂O (1.23 g, 5.46 mmol) was stirred for 1 h at 0° C. Upon completion of the reaction, the resulting solution was diluted with EA (200 mL). The resulting mixture was washed with H₂O (100 mL×3). The mixture was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by combi-flash (EA/PE=0-25%) give the product (4.25 g, 53%). ¹H NMR (300 MHz, CDCl₃) δ 7.63 (s, 1H), 7.37 (s, 1H), 7.30 (s, 1H), 4.62 (q, J=6.1 Hz, 1H), 3.08 (s, 3H), 1.38 (d, J=6.0 Hz, 6H). GCMS (ESI) m/e [M] 292.

Example BB20: Synthesis of 1-bromo-3-methoxy-5-(methylsulfonyl)benzene

Step 1: (3-bromo-5-methoxyphenyl)(methyl)sulfane

A mixture of 1,3-dibromo-5-methoxybenzene (9.00 g, 33.16 mmol), dioxane (100 mL), NaSCH₃ (3.19 g, 33.19 mmol), Pd₂(dba)₃ (1.52 g, 1.66 mmol) and Xantphos (1.92 g, 3.31 mmol) was stirred overnight at 75° C. under nitrogen atmosphere. After cooled to RT, the solvent was removed under vacuum and the residue was purified by combi-flash (EA/PE=0-10%) to give the product (3.2 g, 39%). GCMS (ESI) m/e [M] 232.

Step 2: 1-bromo-3-methoxy-5-(methylsulfonyl)benzene

To a mixture of 1-bromo-3-methoxy-5-(methylsulfanyl)benzene (3.10 g, 12.63 mmol) and THF (30 mL)/H₂O (30 mL) was added NaIO₄ (10.81 g, 50.54 mmol) in H₂O (15 mL) in portions at 0° C., then RuCl₃ (0.14 g, 0.62 mmol) in H₂O (15 mL) was added in portions successively at 0° C. The resulting solution was stirred for 1 h at RT. The resulting solution was diluted with H₂O (50 mL), extracted with EA (30 mL×3), the organic layers were concentrated and purified by combi-flash (EA/PE=0-30%) to give the product (3.22 g, 91%). ¹H NMR (300 MHz, DMSO-d6) δ 7.66 (s, 1H), 7.54 (s, 1H), 7.45 (s, 1H), 3.89 (s, 3H), 3.30 (s, 3H). GCMS (ESI) m/e [M] 264.

Example BB21: Synthesis of 1-bromo-3-methyl-5-(methylsulfonyl)benzene

Step 1: (3-bromo-5-methylphenyl)(methyl)sulfane

A mixture of 1,3-dibromo-5-methylbenzene (11.00 g, 43.13 mmol), dioxane (150 mL), NaSCH₃ (3.02 g, 43.14 mmol), Pd₂(dba)₃ (1.97 g, 2.15 mmol and Xantphos (2.50 g, 4.32 mmol) was stirred overnight at 75° C. under nitrogen atmosphere. After cooled to RT, the solvent was removed under vacuum and the residue was purified by combi-flash (EA/PE=0-8%) to give the product (4.40 g, 42%). GCMS (ESI) m/e [M] 216

Step 2: 1-bromo-3-methyl-5-(methylsulfonyl)benzene

To a mixture of 1-bromo-3-methyl-5-(methylsulfanyl)benzene (4.30 g, 17.82 mmol) and THF (20 mL) was added NaIO₄ (15.25 g, 71.29 mmol) in H₂O (10 mL) in portions at 0° C., then RuCl₃ (0.20 g, 0.89 mmol) in H₂O (10 mL) was added in portions successively at 0° C. The resulting solution was stirred for 1 h at RT. Upon completion of the reaction, the resulting solution was diluted with 50 mL of H₂O, extracted with 3×30 mL of EA and the organic layers were combined and concentrated. The residue was purified by combi-flash (EA/PE=0-20%) to give the product (4.51 g, 96%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.91 (s, 1H), 7.84-7.72 (m, 2H), 3.28 (s, 3H), 2.46-2.40 (m, 3H). GCMS (ESI) m/e [M] 248.

Example BB22: Synthesis of 1-bromo-3-methanesulfonyl-5-(methoxymethyl)benzene

Step 1: 1,3-dibromo-5-(methoxymethyl)benzene

A mixture of 1,3-dibromo-5-(bromomethyl)benzene (7.00 g, 21.28 mmol), MeONa (5.75 g, 106.40 mmol) in MeOH (70 mL) and was stirred for 1 h at 70° C. After cooled to rt, the solvent was removed under vacuum and the residue was diluted with water. The resulting solution was extracted with EA (100 mL×3) and the combined organic layer was washed with brine. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-5%) to give the product (5.00 g, 84%). GCMS (ESI) m/e [M] 280.

Step 2: 1-bromo-3-(methoxymethyl)-5-(methylsulfanyl)benzene

A mixture of 1,3-dibromo-5-(methoxymethyl)benzene (5.00 g, 17.86 mmol), DMF (50 mL) and CH₃SNa (1.50 g, 21.43 mmol) was stirred overnight at RT. Upon completion of the reaction, water (20 mL) was added and the resulting solution was extracted with EA (100 mL×3). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. The solids were filtered out and the resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-2%) to give the product (3.50 g, 79%). GCMS (ESI) m/e [M] 246.

Step 3: 1-bromo-3-methanesulfonyl-5-(methoxymethyl)benzene

A mixture of 1-bromo-3-(methoxymethyl)-5-(methylsulfanyl)benzene (3.50 g, 14.16 mmol), RuCl₃·H₂O (319.26 mg, 1.416 mmol) and NaIO₄ (6.06 g, 28.32 mmol) in THF (35 mL) and H₂O (35 mL) was stirred for 2 h at RT. Upon completion of the reaction, the resulting solution was extracted with EA (100 mL×3) and the organic layers combined. The resulting mixture was washed with brine, dried over anhydrous Na₂SO₄. The resulting mixture was concentrated under vacuum and the residue was purified by combi-flash (EA/PE=0-10%) to give the product (2.21 g, 56%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.75 (s, 1H), 7.70 (s, 1H), 4.50 (s, 2H), 3.45 (s, 3H), 3.03 (s, 3H). GCMS (ESI) m/e [M] 278.

Example BB23: Synthesis of 1-bromo-3-(difluoromethyl)-5-methanesulfonylbenzene

Step 1: 1-bromo-3-(difluoromethyl)-5-(methylsulfanyl)benzene

A mixture of 1,3-dibromo-5-(difluoromethyl)benzene (4.20 g, 14.69 mmol), (methylsulfanyl) sodium (927 mg, 13.22 mmol), DIEA (3.80 g, 29.38 mmol), Xantphos (849.97 mg, 1.47 mmol), Pd₂(dba)₃ (672.58 mg, 0.74 mmol) and 1,4-dioxane (50 mL) was stirred overnight at 80° C. under nitrogen atmosphere. After cooled to RT, the resulting mixture was extracted with EA (150 mL×3) and the combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-10%) to give the product (2.60 g, 69%). GCMS (ESI) m/e [M] 252

Step 2: 1-bromo-3-(difluoromethyl)-5-methanesulfonylbenzene

To a stirred solution of 1-bromo-3-(difluoromethyl)-5-(methylsulfanyl)benzene (2.60 g, 10.27 mmol) in THF (40 ml) and H₂O (40 mL) were added RuCl₃·H₂O (69.48 mg, 0.31 mmol) and NaIO₄ (4.39 g, 20.55 mmol) in portions at 0° C. The resulting mixture was stirred for 2 h at 0° C. Upon completion of the reaction, the resulting mixture was filtered out and the filtrate was concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-40%) to give the product (1.79 g, 61%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.31 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.20-7.10 (m, 1H), 3.37 (s, 3H).

Example BB24: Synthesis of 3-bromo-5-methanesulfonylbenzonitrile

Step 1: 3-bromo-5-(methylsulfanyl)benzonitrile

A mixture of 3,5-dibromobenzonitrile (10.00 g, 38.32 mmol), dioxane (160 mL), (methylsulfanyl) sodium (2.42 g, 34.53 mmol), Pd₂(dba)₃ (1.75 g, 1.91 mmol) and Xantphos (2.22 g, 3.83 mmol) was stirred overnight at 75° C. in an oil bath. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with water (20 mL). The resulting solution was extracted with EA (100 mL×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (EA/PE=0-9%) to give the product (8.52 g, 88%). LCMS (ESI, m/e) [M+1]⁺ 228.

Step 2: 3-bromo-5-methanesulfonylbenzonitrile

To a mixture of 3-bromo-5-(methylsulfanyl) benzonitrile (8.52 g, 37.35 mmol) and THF (75 mL) were added NaIO₄ (23.97 g, 112.06 mmol) in H₂O (35 mL) and RuCl₃ (0.25 g, 1.12 mmol) in H₂O (35 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at RT. Upon completion of the reaction, the resulting solution was extracted with EA (100 mL×3) and then concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-38%) to give the product (4.40 g, 40%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.55 (s, 1H), 8.45-8.32 (m, 2H), 3.36 (s, 3H). LCMS (ESI, m/e) [M+1]⁺ 260.

Example BB25: Synthesis of 1-bromo-3-methanesulfonyl-5-(trifluoromethoxy)benzene

Step 1: 1-bromo-3-(methylsulfanyl)-5-(trifluoromethoxy)benzene

A mixture of 1,3-dibromo-5-(trifluoromethoxy)benzene (5.00 g, 15.63 mmol), 1,4-dioxane (50 mL), CH₃SNa (984.67 mg, 14.07 mmol), Pd₂(dba)₃ (715.62 mg, 0.78 mmol) and XantPhos (904.37 mg, 1.56 mmol) was stirred for 2 h at 75° C. under nitrogen atmosphere. After cooled to room temperature, the solvent was removed and the residue was diluted with water. The resulting solution was extracted with of EA (150 mL) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (EA/PE=0-5%) to give the product (3.00 g, 67%). GCMS (ESI) m/e [M] 286.

Step 2: 1-bromo-3-methanesulfonyl-5-(trifluoromethoxy)benzene

A mixture of 1-bromo-3-(methylsulfanyl)-5-(trifluoromethoxy)benzene (3.00 g, 10.45 mmol), RuCl₃·H₂O (235.58 mg, 1.05 mmol), NaIO₄ (6.71 g, 31.35 mmol), H₂O (30 mL) in THF (30 mL) was stirred for 2 h at RT. Upon completion of the reaction, the resulting solution was extracted with EA (100 mL×3) and the organic layers combined. The resulting mixture was washed with brine, dried over anhydrous Na₂SO₄. The resulting mixture was concentrated under vacuum and the residue was purified by combi-flash (EA/PE=0-15%) to give the product (2.31 g, 69%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.75 (s, 1H), 7.70 (s, 1H), 3.10 (s, 3H). GCMS (ESI) m/e [M] 318.

Example BB26: Synthesis of 2-bromo-4-[(2R)-2-[(tert-butyldimethylsilyl)oxy]propoxy]-6-methanesulfonylpyridine

A mixture of 2-bromo-6-methanesulfonylpyridin-4-ol (1.00 g, 3.97 mmol), (2R)-2-[(tert-butyldimethylsilyl)oxy]propyl 4-methylbenzenesulfonate (2.73 g, 7.94 mmol) and Cs₂CO₃ (2.59 g, 7.90 mmol) in DMF (10 mL) was stirred at 100° C. overnight under nitrogen atmosphere. After cooled to room temperature, the solvent was removed and the residue was diluted with water. The resulting solution was extracted with EA (50 mL×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by Prep-TLC (PE/EA=5:1) to give the product (644 mg, 82%). ¹H NMR (300 MHz, CDCl₃) δ 7.55 (s, 1H), 7.18 (s, 1H), 4.26-4.11 (m, 1H), 4.03-3.89 (m, 2H), 3.24 (s, 3H), 1.24 (d, J=6.3 Hz, 3H), 0.88 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 424.

Example BB27: Synthesis of 7-bromo-2H,3H-[1,4]dioxino[2,3-c]pyridine

Step 1: 2-[(6-bromo-4-iodopyridin-3-yl) oxy] ethanol

To a mixture of 2-bromo-5-fluoro-4-iodopyridine (11.00 g, 36.43 mmol) in NMP (135 mL) were added ethylene glycol (10.81 g, 174.16 mmol) and t-BuOK (4.50 g, 40.08 mmol) in NMP (30 mL) dropwise at 0° C. The resulting solution was stirred for 1 h at 80° C. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with water (300 mL). The resulting solution was extracted with EA (200 mL×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (EA/PE=0-41%) to give the product (12.00 g, 86%). LCMS (ESI, m/e) [M+1]⁺ 344.

Step 2: 7-bromo-2H,3H-[1,4]dioxino[2,3-c]pyridine

A mixture of 2-[(6-bromo-4-iodopyridin-3-yl) oxy] ethanol (12.00 g, 34.89 mmol), i-PrOH (180.00 mL), 3,4,7,8-tetramethyl-1,10-phenantholine (0.68 g, 2.88 mmol), CuI (0.41 g, 2.13 mmol) and t-BuOK (5.48 g, 48.85 mmol) was stirred for 1 h at 80° C. under nitrogen atmosphere. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with water (20 mL). The resulting solution was extracted with EA (300 mL×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (EA/PE=0-7%) to give the product (1.36 g, 16%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.95 (s, 1H), 7.19 (s, 1H), 4.44-4.24 (m, 4H). LCMS (ESI, m/e) [M+1]⁺ 216.

Example BB29: Synthesis of 2-bromo-4-chloro-6-(methylsulfonyl)pyridine

Step 1: 2-bromo-6-(methylthio)pyridin-4-amine

A mixture of 2,6-dibromopyridin-4-amine (5.00 g, 19.85 mmol), Cs₂CO₃ (9.70 g, 29.77 mmol) and MeSNa (1.53 g, 21.83 mmol) in DMSO (50 mL) was stirred for 12 h at 80° C. After cooled to room temperature, water was added and the resulting mixture was extracted with EA (500 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum and the residue was used in the next step directly without further purification. LCMS (ESI) m/e [M+1]⁺ 219.

Step 2: 2-bromo-6-(methylsulfonyl)pyridin-4-amine

To a solution of 2-bromo-6-(methylsulfanyl)pyridin-4-amine (2.50 g, 11.41 mmol) in THF (25 mL) was added RuCl₃·H₂O (77.17 mg, 0.34 mmol), NaIO₄ (9.76 g, 45.64 mmol) and H₂O (25 mL) at 0° C. and the resulting mixture was stirred at room temperature for 1 h. Upon completion of the reaction, the resulting mixture was extracted with EA (300 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by combi-flash (EA/PE=1:1) to give the product (1.02 g, 35%). LCMS (ESI) m/e [M+1]⁺ 251.

Step 3: 2-bromo-4-chloro-6-(methylsulfonyl)pyridine

To a solution of 2-bromo-6-methanesulfonylpyridin-4-amine (800 mg, 3.18 mmol) in HCl (12M, 14.4 mL) was added NaNO₂ (1.10 g, 15.93 mmol) at 0° C. and the mixture was stirred for 1 h at this temperature. Upon completion of the reaction, the resulting mixture was extracted with EA (100 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by Prep-TLC (EA/PE=1:4) to give the product (468 mg, 54%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.33 (s, 1H), 8.17 (s, 1H), 3.33 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 270.

Example BB30: Synthesis of 1-bromo-3-fluoro-5-methanesulfonylbenzene

Step 1: 1-bromo-3-fluoro-5-(methylsulfanyl)benzene

A mixture of 1-bromo-3,5-difluorobenzene (5.00 g, 25.91 mmol), (methylsulfanyl)sodium (1.82 g, 25.91 mmol) in DMF (50 mL) was stirred for 2 h at RT. Upon completion of the reaction, water was added and the resulting solution was extracted with EA (100 mL×3) and the organic layers combined. The resulting mixture was washed with brine, dried over anhydrous Na₂SO₄. The solid were filtered out and the resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-2%) to give the product (4.80 g, 84%). GCMS (ESI) m/e [M] 220.

Step 2: 1-bromo-3-fluoro-5-methanesulfonylbenzene

To a mixture of 1-bromo-3-fluoro-5-(methylsulfanyl)benzene (4.80 g, 21.71 mmol) and THF (50 mL)/H₂O (50 mL) were added RuCl₃·H₂O (489 mg, 2.17 mmol) and NaIO₄ (13.93 g, 65.13 mmol) in several batches at 0° C. The resulting solution was stirred for 2 h at RT. Upon completion of the reaction, water was added and the resulting solution was extracted with EA (100 mL×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (EA/PE=0-15%) to give the product (4.60 g, 80%). ¹H NMR (300 MHz, CDCl₃) δ 7.91 (s, 1H), 7.60-7.50 (m, 2H), 3.13 (s, 3H). GCMS (ESI) m/e [M] 252.

Example BB31: Synthesis of 1-bromo-3-chloro-5-(methylsulfonyl)benzene

Step 1: 1-bromo-3-chloro-5-(methylsulfanyl)benzene

A mixture of 1,3-dibromo-5-chlorobenzene (10.00 g, 36.98 mmol), DMF (200 mL) and MeSNa (2.59 g, 37.00 mmol) was stirred for 1 h at RT. Upon completion of the reaction, the resulting solution was diluted with EA (200 mL) and the resulting mixture was washed with H₂O (200 mL×3). The mixture was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by combi-flash (EA/PE=0-15%) give the product (7.6 g, 87%). GCMS (ESI) m/e [M] 236.

Step 2: 1-bromo-3-chloro-5-methanesulfonylbenzene

A mixture of 1-bromo-3-chloro-5-(methylsulfanyl)benzene (7.60 g, 31.99 mmol), THF (60 mL), H₂O (60 mL), NaIO₄ (27.37 g, 127.96 mmol) and RuCl₃·H₂O (1.44 g, 6.39 mmol) was stirred for 1 h at 0° C. Upon completion of the reaction, the resulting solution was diluted with EA (200 mL) and the resulting mixture was washed with H₂O (200 mL×3). The mixture was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by combi-flash (EA/PE=0-30%) give the product (1.13 g, 13%). ¹H NMR (400 MHz, CDCl₃) δ 7.91 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 3.02 (s, 3H). GCMS (ESI) m/e [M]268.

Example BB32: Synthesis of 1-bromo-3-cyclopropoxy-5-methanesulfonylbenzene

Step 1: 1,3-dibromo-5-cyclopropoxybenzene

A mixture of 3,5-dibromophenol (5.00 g, 19.85 mmol), cyclopropyltrifluoro-lambda4-borane potassium (11.75 g, 79.40 mmol), K₂CO₃ (5.49 g, 39.70 mmol), 1,10-phenantholine (357.69 mg, 1.99 mmol) and Cu(OAc)₂ (360.5 mg, 1.985 mmol) in toluene (45 mL) and H₂O (15 mL) was stirred for overnight at 70° C. under nitrogen atmosphere. After cooled to room temperature, water was added and the resulting solution was extracted with EA (200 mL×3) and the combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. The solids were filtered out and the resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-5%) to give the product (1.00 g, 17%). GCMS (ESI) m/e [M] 290.

Step 2: 1-bromo-3-cyclopropoxy-5-(methylsulfanyl)benzene

A mixture of 1,3-dibromo-5-cyclopropoxybenzene (1.00 g, 3.43 mmol), 1,4-dioxane (10 mL), CH₃SNa (191.8 mg, 2.74 mmol), Xantphos (396.35 mg, 0.69 mmol) and Pd₂(dba)₃ (313.6 mg, 0.34 mmol) was stirred for 2 h at 75° C. under nitrogen atmosphere. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with 40 mL of water. The resulting solution was extracted with EA (60 mL×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (EA/PE=0-5%) to give the product (300 mg, 34%). GCMS (ESI) m/e [M] 258.

Step 3: 1-bromo-3-cyclopropoxy-5-methanesulfonylbenzene

To a mixture of 1-bromo-3-cyclopropoxy-5-(methylsulfanyl)benzene (300 mg, 1.16 mmol) in THF (5 mL)/H₂O (5 mL) were added RuCl₃·H₂O (26 mg, 0.12 mmol) at 0° C. Then NaIO₄ (742.79 mg, 3.47 mmol) was added in several batches at 0° C. The resulting solution was stirred for 2 h at RT. Upon completion of the reaction, water was added and the resulting solution was extracted with EA (30 mL×3) and the organic layers combined. The resulting mixture was washed with brine, dried over anhydrous Na₂SO₄. The resulting mixture was concentrated under vacuum and the residue was purified by Prep-TLC (EA/PE=1:2) to give the product (165 mg, 49%). ¹H NMR (300 MHz, CDCl₃) δ 7.69 (s, 1H), 7.55 (s, 1H), 7.49 (s, 1H), 3.85-3.81 (m, 1H), 3.09 (s, 3H), 0.94-0.76 (m, 4H). GCMS (ESI) m/e [M] 290.

Example BB33: Synthesis of of 2-bromo-3-isopropoxy-6-methanesulfonylpyridine

Step 1: 2-bromo-6-iodo-3-isopropoxypyridine

A mixture of 2-bromo-6-iodopyridin-3-ol (10.00 g, 33.34 mmol), DMF (150 mL), 2-iodopropane (13.04 g, 76.70 mmol) and Cs₂CO₃ (21.73 g, 66.69 mmol) was stirred for 3 h at 80° C. After cooled to room temperature, water was added and the resulting solution was extracted with EA (100 mL×3). The resulting mixture was concentrated under vacuum to give the product (11.08 g, 87%). LCMS (ESI, m/e) [M+1]⁺ 342.

Step 2: 2-bromo-3-isopropoxy-6-(methylsulfanyl)pyridine

A mixture of 2-bromo-6-iodo-3-isopropoxypyridine (11.08 g, 32.40 mmol), 1,4-dioxane (166 mL), (methylsulfanyl)sodium (1.82 g, 25.97 mmol), Pd₂(dba)₃ (1.48 g, 1.62 mmol), Xantphos (1.87 g, 3.24 mmol) was stirred for 3 h at 75° C. nitrogen atmosphere. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with water (20 mL). The resulting solution was extracted with EA (30 mL×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (EA/PE=10:1) to give the product (8.00 g, 84%). LCMS (ESI, m/e) [M+1]⁺ 262.

Step 3: 2-bromo-3-isopropoxy-6-methanesulfonylpyridine

To a mixture of 2-bromo-3-isopropoxy-6-(methylsulfanyl)pyridine (5.00 g, 19.07 mmol) in THF (50.00 mL) was added NaIO₄ (12.24 g, 57.22 mmol) and RuCl₃ (0.13 g, 0.57 mmol) in H₂O (30 mL) dropwise at 0° C. and the resulting solution was stirred for 1 h at RT. Upon completion of the reaction, the resulting solution was extracted EA (30 mL×3) and the combined organic layers were concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-24%) to give the product (3.10 g, 50%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.02 (d, J=8.5 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 4.95-4.91 (m, 1H), 3.25 (s, 3H), 1.37 (d, J=6.0 Hz, 6H). LCMS (ESI, m/e) [M+1]⁺ 294.

Example BB34: Synthesis of 2-bromo-4-(cyclopropylmethoxy)-6-methanesulfonyl pyridine

A mixture of 2-bromo-6-methanesulfonylpyridin-4-ol (1.00 g, 3.97 mmol), Cs₂CO₃ (2.59 g, 7.94 mmol) and (bromomethyl)cyclopropane (0.80 g, 5.95 mmol) in DMF (10 mL) was stirred for 5 h at 80° C. under nitrogen atmosphere. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with 50 mL of water. The resulting solution was extracted with EA (30 mL×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by Prep-TLC (PE/EA=5:1) to give the product (793 mg, 65%). ¹H NMR (300 MHz, CDCl₃) δ 7.54 (s, 1H), 7.16 (s, 1H), 3.94 (d, J=7.1 Hz, 2H), 3.23 (s, 3H), 1.35-1.22 (m, 1H), 0.77-0.65 (m, 2H), 0.43-0.34 (m, 2H). LCMS (ESI) m/e [M+1]⁺ 306.

Example BB35: Synthesis of 1-bromo-3-(cyclopropylmethoxy)-5-(methylsulfonyl) benzene

Step 1: 1,3-dibromo-5-(cyclopropylmethoxy)benzene

A mixture of 3,5-dibromophenol (5.00 g, 19.85 mmol), DMF (50 mL), (bromomethyl)cyclopropane (8.04 g, 59.55 mmol) and K₂CO₃ (5.49 g, 39.72 mmol) was stirred for 2 h at 80° C. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with water (100 mL). The resulting solution was extracted with EA (30 mL×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (EA/PE=0-15%) give the product (2.80 g, 46%). GCMS (ESI) m/e [M+1]⁺ 304.

Step 2: (3-bromo-5-(cyclopropylmethoxy)phenyl)(methyl)sulfane

A mixture of 1,3-dibromo-5-(cyclopropylmethoxy)benzene (2.80 g, 9.15 mmol), 1,4-dioxane (20 mL), Pd₂(dba)₃ (418 mg, 0.46 mmol), Xantphos (529 mg, 0.915 mmol) and MeSNa (641 mg, 9.15 mmol) was stirred for 4 h at 80° C. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with water (20 mL). The resulting solution was extracted with EA (30 mL×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (EA/PE=0-15%) give the product (2.0 g, 80%). LCMS (ESI) m/e [M+1]⁺ 272.

Step 3: 1-bromo-3-(cyclopropylmethoxy)-5-(methylsulfonyl)benzene

A mixture of 1-bromo-3-(cyclopropylmethoxy)-5-(methylsulfanyl)benzene (2.00 g, 7.32 mmol), NaIO₄ (6.26 g, 29.27 mmol), RuCl₃·H₂O (330 mg, 1.46 mmol) in THF (20 mL) and H₂O (20 mL) was stirred for 1 h at 0° C. Upon completion of the reaction, EA (100 mL) was added and the resulting mixture was washed with water (100 mL×3). The mixture was dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by combi-flash (EA/PE=0-20%) to give the product (1.07 g, 48%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.61 (s, 1H), 7.52 (s, 1H), 7.42 (s, 1H), 3.96 (d, J=7.1 Hz, 2H), 3.28 (s, 3H), 1.30-1.13 (m, 1H), 0.63-0.53 (m, 2H), 0.39-0.30 (m, 2H).

Example BB36: Synthesis of 2-bromo-4-cyclobutoxy-6-(methylsulfonyl)pyridine

A solution of 2-bromo-6-methanesulfonylpyridin-4-ol (700 mg, 2.78 mmol), bromocyclobutane (749 mg, 5.55 mmol) and K₂CO₃ (767 mg, 5.55 mmol) in DMF (7 mL) was stirred for 8 h at 80° C. After cooled to room temperature, water was added and the resulting mixture was extracted with EA (200 mL×3). The combined organic layers were washed with brine (200 mL×3), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum. The residue was purified by Prep-TLC (EA/PE=1:3) to give the product (382 mg, 45%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.49 (s, 1H), 7.41 (s, 1H), 5.07-4.95 (m, 1H), 3.28 (s, 3H), 2.51-2.41 (m, 1H), 2.16-2.02 (m, 2H), 1.83-1.80 (m, 1H), 1.74-1.58 (m, 1H). LCMS (ESI) m/e [M+1]⁺ 306.

Example BB37: Synthesis of 2-bromo-4-(cyclopentyloxy)-6-methanesulfonylpyridine

To a stirred solution of 2-bromo-6-methanesulfonylpyridin-4-ol (500 mg, 1.98 mmol), PPh₃ (780 mg, 2.97 mmol) and cyclopentanol (188 mg, 2.18 mmol) in THF (10 mL) was added DIAD (642 mg, 3.17 mmol) dropwise at 0° C. and the resulting mixture was stirred overnight at 50° C. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with water (20 mL). The resulting solution was extracted with EA (30 mL×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by Prep-TLC (PE/EA=5:1) to give the product (300 mg, 47%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.53 (s, 1H), 7.46 (s, 1H), 5.14-5.10 (m, 1H), 3.27 (s, 3H), 2.04-1.89 (m, 3H), 1.82-1.51 (m, 5H). LCMS (ESI) m/e [M+1]⁺ 320.

Example BB38: Synthesis of 2-bromo-6-methanesulfonyl-4-(oxolan-3-yloxy)pyridine

To a stirred solution of 2-bromo-6-methanesulfonylpyridin-4-ol (400 mg, 1.59 mmol) and 3-hydroxytetrahydrofuran (154 mg, 1.75 mmol) in THF were added PPh₃ (832 mg, 3.17 mmol) and DIAD (642 mg, 3.17 mmol) dropwise portions at 0° C. The resulting mixture was stirred overnight at RT. Upon completion of the reaction, water was added and the resulting mixture was extracted with EA (50 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over anhydrous Na₂SO₄, concentrated under vacuum. The residue was purified by Prep-TLC (PE/EA=1:1) to give the product (250 mg, 47%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.60 (s, 1H), 7.51 (s, 1H), 5.38-5.34 (m, 1H), 3.90-3.82 (m, 3H), 3.82-3.72 (m, 1H), 3.28 (s, 3H), 2.29-2.25 (m, 1H), 2.00-1.95 (m, 1H). LCMS (ESI) m/e [M+1]322.

Example BB39: Synthesis of 2-bromo-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine

Step 1: 2,6-dibromo-N-methoxy-N-methylisonicotinamide

A mixture of 2,6-dibromoisonicotinic acid (9 g, 32.0 mmol) and CDI (5.7 g, 35.0 mmol) in DCM (100 mL) was stirred at 20° C. for 2 h, N,O-dimethylhydroxylamine hydrochloride (3.4 g, 35.0 mmol) was added and stirred at 20° C. for 12 h. The mixture was diluted with H₂O (100 mL) and extracted with DCM (100 mL×3). The combined organic layers were dried over Na₂SO₄ and concentrated to give the product (7.3 g, 70%). ¹H NMR (400 MHz, CDCl₃) δ 7.68 (s, 2H), 3.58 (s, 3H), 3.37 (s, 3H). MS (ESI) m/e [M+1]⁺ 324.

Step 2: 1-(2,6-dibromopyridin-4-yl)ethanone

A mixture of 2,6-dibromo-N-methoxy-N-methylisonicotinamide (4.0 g, 12.3 mmol) in THF (40 mL) was added MgBrCH₃ (41 mL, 123 mmol, 3M) dropwise at 0° C. The mixture was stirred at 20° C. for 2 h. The mixture was diluted with H₂O (50 ml) and extracted with EA (50 mL×3). The combined organic layers were dried over Na₂SO₄ and concentrated to give the product (3.2 g, 93%). ¹H NMR (400 MHz, CDCl₃) δ 7.87 (s, 2H), 2.61 (s, 3H). MS (ESI) m/e [M+1]⁺ 278.

Step 3: 1-(2,6-dibromopyridin-4-yl)ethanol

A solution of 1-(2,6-dibromopyridin-4-yl)ethanone (3.2 g, 11.5 mmol) in MeOH (30 mL) at 0° C., was added NaBH₄ (434 mg, 11.5 mmol). The mixture was stirred at 0° C. for 30 mins. The mixture was diluted with H₂O (50 ml) and extracted with EA (50 mL×3). The combined organic layers were dried over Na₂SO₄ and concentrated to give the product (3.2 g, 99%). MS (ESI) m/e [M+1]⁺ 282.

Step 4: 2,6-dibromo-4-(1-methoxyethyl)pyridine

A solution of 1-(2,6-dibromopyridin-4-yl)ethanol (3.2 g, 11.4 mmol) in THF (50 mL) at 0° C., was added NaH (60% in mineral oil, 592 mg, 14.8 mmol). The mixture was stirred at 0° C. for 20 min. Mel (4.9 g, 34.2 mmol) was added and stirred at 20° C. for 2 h. The mixture was diluted with sat. NH₄Cl (50 ml) and extracted with EA (50 mL×3). The combined organic layers were dried over Na₂SO₄ and concentrated to give the crude product (3.2 g, crude), used directly. MS (ESI) m/e [M+1]⁺ 294.

Step 5: 2-bromo-4-(1-methoxyethyl)-6-(methylthio)pyridine

A solution of 2,6-dibromo-4-(1-methoxyethyl)pyridine (1.5 g, 5.1 mmol) in DMF (20 mL) at 20° C., was added NaSCH₃ (392 mg, 5.6 mmol). The mixture was stirred at 20° C. for 1 h. The mixture was diluted with brine (20 mL) and extracted with EA (20 mL×3). The combined organic layers were dried over Na₂SO₄ and concentrated to give the product (1.5 g, crude), used directly. MS (ESI) m/e [M+1]⁺ 262.0.

Step 6: 2-bromo-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine

A mixture of 2-bromo-4-(1-methoxyethyl)-6-(methylthio)pyridine (1.5 g, 5.1 mmol) and oxone (12.5 g, 20.4 mmol) in MeOH (16 mL) and H₂O (8 ml) was stirred at 20° C. for 12 h. The mixture was filtered, added brine (20 ml) and extracted with EA (20 mL×3). The combined organic layers were dried over Na₂SO₄ and concentrated. The crude was purified by column chromatography (PE/EA=20:1-3:1) to give the product (1.1 g, 65%). ¹H NMR (400 MHz, CDCl₃) δ 7.97 (s, 1H), 7.70 (s, 1H), 4.39-4.35 (m, 1H), 3.33 (s, 3H), 3.28 (s, 3H), 1.45 (d, J=6.4 Hz, 3H). MS (ESI) m/e [M+1]⁺ 294.

Example BB40: Synthesis of 2-bromo-4-[(2S)-butan-2-yloxy]-6-methanesulfonyl pyridine

To a stirred solution of 2-bromo-6-methanesulfonylpyridin-4-ol (400 mg, 1.59 mmol), (S)-2-butanol (176 mg, 2.38 mmol) and PPh₃ (624 mg, 2.38 mmol) in THF (10 mL) was added DIAD (513 mg, 2.54 mmol) dropwise at 0° C. under air atmosphere. The resulting mixture was stirred overnight at 50° C. The resulting mixture was extracted with EA (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated and purified by silica gel column chromatography (PE/EA=8:1) to give 2-bromo-4-[(2S)-butan-2-yloxy]-6-methanesulfonylpyridine (358 mg, 73% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.58 (s, 1H), 7.48 (s, 1H), 4.86-4.71 (m, 1H), 3.27 (s, 3H), 1.77-1.52 (m, 2H), 1.27 (d, J=6.1 Hz, 3H), 0.91 (t, J=7.4 Hz, 3H). LCMS (ESI) m/e [M+1]⁺ 308.

Example BB41: Synthesis of 2-bromo-4-(difluoromethoxy)-6-methanesulfonylpyridine

A mixture solution of KOH (1.11 g, 19.78 mmol), CH₃CN (5 mL) and H₂O (5 mL) was cooled to approximately −10° C. 2-bromo-6-methanesulfonylpyridin-4-ol (500 mg, 1.98 mmol) was added dropwise followed by diethyl bromodifluoromethylphosphonate (1.06 g, 3.97 mmol) over 15 mins. The mixture was allowed to warm to RT over 1 h. The mixture was poured into water and extracted with EA (50 mL×3), washed with brine and dried over Na₂SO₄. The residue was purified by Prep-TLC (EA/PE=1:10) to give 2-bromo-4-(difluoromethoxy)-6-methanesulfonyl pyridine (310 mg, 52% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.94 (t, J=1.8 Hz, 1H), 7.88-7.50 (m, 2H), 3.34 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 301.

Example BB42: Synthesis of 2-bromo-4-ethoxy-6-methanesulfonylpyridine

A mixture solution of 2-bromo-6-methanesulfonylpyridin-4-ol (3.50 g, 13.88 mmol), Cs₂CO₃ (9.10 g, 27.84 mmol) and ethyl iodide (3.26 g, 20.90 mmol) in DMF (40 mL) was stirred for 1 h at 80° C. The mixture was allowed to cool down to rt. The resulting mixture was extracted with EA (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (EA/PE=20-25%) to give 2-bromo-4-ethoxy-6-methanesulfonylpyridine (3.05 g, 78% yield). 1H NMR (300 MHz, CDCl₃) δ 7.55 (d, J=2.2 Hz, 1H), 7.17 (d, J=2.2 Hz, 1H), 4.19 (m, 2H), 3.25 (s, 3H), 1.49 (t, J=7.0 Hz, 3H). LCMS (ESI) m/e [M+1]⁺ 281.

Example BB43: Synthesis of [[(2R)-1-(3-bromo-5-methanesulfonylphenoxy)propan-2-yl]oxy](tert-butyl)dimethylsilane

Step 1: (2R)-1-[(4-methylbenzenesulfonyl)oxy]propan-2-ol

To a stirred solution of R-1, 2-propanediol (5.00 g, 65.71 mmol) in Py (50 mL) was added TsCl (13.78 g, 72.28 mmol) in portions at 0° C. The resulting mixture was stirred overnight at RT. The resulting mixture was extracted with EA (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated and purified by combi-flash (EA/PE=28-32%) to give (2R)-1-[(4-methylbenzenesulfonyl)oxy]propan-2-ol (10.0 g, 66% yield). LCMS (ESI) m/e [M+1]⁺ 230.

Step 2: (2R)-2-[(tert-butyldimethylsilyl)oxy]propyl 4-methylbenzenesulfonate

To a stirred mixture of (2R)-1-[(4-methylbenzenesulfonyl)oxy]propan-2-ol (10 g, 43.42 mmol), Imidazole (8.87 g, 130.28 mmol) in DCM (100 mL) was added TBSCl (19.64 g, 130.28 mmol) in portions at 0° C. The resulting mixture was stirred for 1 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by combi-flash (EA/PE=3-5%) to give the crude product (15.00 g, 100% yield). LCMS (ESI) m/e [M+1]⁺ 344.

Step 3: tert-butyl([[(2R)-1-(3,5-dibromophenoxy)propan-2-yl]oxy])dimethylsilane

A mixture of 3,5-dibromophenol (2.0 g, 7.94 mmol) and (2R)-2-[(tert-butyldimethylsilyl)oxy]propyl 4-methylbenzenesulfonate (5.46 g, 15.85 mmol) and Cs₂CO₃ (5.17 g, 15.86 mmol) in DMF (20 mL) was stirred for one night at 100° C. The mixture was allowed to cool down to RT. The resulting mixture was extracted with EA (40 mL×3). The combined organic layers were washed with brine (40 mL×2), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (EA/PE=3-5%) to give tert-butyl([[(2R)-1-(3,5-dibromophenoxy)propan-2-yl]oxy])dimeth ylsilane (1.90 g, 56% yield).

Step 4: [[(2R)-1-[3-bromo-5-(methylsulfanyl)phenoxy]propan-2-yl]oxy](tert-butyl) dimethylsilane

A mixture of tert-butyl([[(2R)-1-(3,5-dibromophenoxy)propan-2-yl]oxy])dimethylsilane (1.00 g, 2.36 mmol), (methylsulfanyl)sodium (166 mg, 2.37 mmol), DIEA (0.82 mL, 4.71 mmol), Pd₂(dba)₃ (108 mg, 0.12 mmol) and Xantphos (137 mg, 0.24 mmol) in dioxane (10 mL) was stirred for 4 h at 70° C. under N₂ atmosphere. The mixture was allowed to cool down to RT. The resulting mixture was extracted with EA (40 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA=20:1) to give [[(2R)-1-[3-bromo-5-(methylsulfanyl)phenoxy]propan-2-yl]oxy](tert-butyl)dimethylsilane (470 mg, 50% yield).

Step 5: [[(2R)-1-(3-bromo-5-methanesulfonylphenoxy)propan-2-yl]oxy](tert-butyl) dimethylsilane

To a stirred solution of [[(2R)-1-[3-bromo-5-(methylsulfanyl)phenoxy]propan-2-yl]oxy](tert-butyl)dimethylsilane (470 mg, 1.20 mmol) in THF (30 mL) were added RuCl₃·H₂O (7.5 mg, 0.04 mmol) and NaIO₄ (513.6 mg, 2.40 mmol) in H₂O (20 mL) at 0° C. and the resulting solution was stirred for 1 h at 0° C. Then the mixture was extracted with EA (30 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over Na₂SO₄. After filtration, the filtrate was concentrated and purified by Prep-TLC (PE/EA=10:1) to give [[(2R)-1-(3-bromo-5-methanesulfonyl phenoxy)propan-2-yl]oxy](tert-butyl)dimethylsilane (344.2 mg, 67% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.66 (s, 1H), 7.38 (s, 1H), 7.33 (s, 1H), 4.23-4.15 (m, 1H), 3.96-3.81 (m, 2H), 3.08 (s, 3H), 1.29-1.23 (d, J=8.0 Hz, 3H), 0.91 (s, 9H), 0.10 (s, 6H). LCMS (ESI) m/e [M+1]⁺ 422.

Example BB44: Synthesis of 2-bromo-6-(ethanesulfonyl)-4-isopropoxypyridine

Step 1: 2-bromo-6-(ethylsulfanyl)pyridin-4-ol

A stirred mixture of 2, 6-dibromopyridin-4-ol (5.00 g, 19.77 mmol), EtSNa (1.66 g, 19.77 mmol), Pd₂(dba)₃ (181 mg, 0.20 mmol), Xantphos (114.4 mg, 0.20 mmol) and DIEA (6.9 mL, 53.29 mmol) in dioxane (50 mL) was stirred for 3 h at 80° C. The mixture was allowed to cool down to RT. The resulting mixture was extracted with EA (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give 2-bromo-6-(ethylsulfanyl)pyridin-4-ol as a crude product, and used in the next step directly without further purification. LCMS (ESI) m/e [M+1]⁺ 234.

Step 2: 2-bromo-6-(ethanesulfonyl)pyridin-4-ol

To a stirred mixture of 2-bromo-6-(ethylsulfanyl)pyridin-4-ol (5.00 g, 21.36 mmol) in THF was added RuCl₃·H₂O (133 mg, 0.64 mmol) in water for a moment and NaIO₄ (9.14 g, 42.72 mmol) was added in THF and water in portions at 0° C. for 30 mins. The resulting mixture was extracted with EA (100 mL×3). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (EA/PE=28-32%) to 2-bromo-6-(ethanesulfonyl)pyridin-4-ol (2.00 g, 35% yield). LCMS (ESI) m/e [M+1]⁺ 266.

Step 3: 2-bromo-6-(ethanesulfonyl)-4-isopropoxypyridine

A stirred solution of 2-bromo-6-(ethanesulfonyl)pyridin-4-ol (1.50 g, 5.64 mmol), Cs₂CO₃ (3.68 g. 11.27 mmol) and 2-iodopropane (1.44 g. 8.46 mmol) in dimethylformamide (10 mL) at 80° C. for 1 h. The mixture was allowed to cool down to rt. The resulting mixture was extracted with EA (40 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (EA/PE=28-32%) to give 2-bromo-6-(ethanesulfonyl)-4-isopropoxypyridine (1.40 g, 78% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.53 (s, 1H), 7.13 (s, 1H), 4.75-4.70 (m, 1H), 3.46-3.42 (m, 2H), 1.41 (d, J=6.1 Hz, 6H), 1.35-1.32 (m, 3H). LCMS (ESI) m/e [M+1]⁺ 307.

Example BB45: Synthesis of [[(2S)-1-(3-bromo-5-methanesulfonylphenoxy)propan-2-yl]oxy](tert-butyl)dimethylsilane

Step 1: (2S)-1-[(4-methylbenzenesulfonyl)oxy]propan-2-ol

To a stirred solution of (S)-1, 2-propanediol (5.00 g, 65.71 mmol) in Py (50 mL) was added TsCl (13.78 g, 72.28 mmol) in portions at 0° C. The resulting mixture was stirred overnight at RT. The resulting mixture was extracted with EA (100 mL×3). The combined organic layers were washed with brine (100×3 mL), dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by combi-flash (EA/PE=28-32%) to give (2S)-1-[(4-methylbenzenesulfonyl)oxy]propan-2-ol (10.00 g, 66% yield). LCMS (ESI) m/e [M+1]⁺ 230.

Step 2: (2S)-2-[(tert-butyldimethylsilyl)oxy]propyl 4-methylbenzenesulfonate

To a stirred mixture of (2S)-1-[(4-methylbenzenesulfonyl)oxy]propan-2-ol (10.00 g, 43.42 mmol), Imidazole (8.87 g, 130.28 mmol) and in DCM (100 mL) was added TBSCl (19.64 g, 130.28 mmol) in portions at 0° C. The resulting mixture was stirred for 1 h at RT. The mixture was concentrated and purified by combi-flash (EA/PE=3-5%) to give (2S)-2-[(tert-butyldimethylsilyl)oxy] propyl-4-methylbenzenesulfonate (15.00 g, 100% yield). LCMS (ESI) m/e [M+1]⁺ 344.

Step 3: tert-butyl([[(2S)-1-(3,5-dibromophenoxy)propan-2-yl]oxy])dimethylsilane

A mixture of 3, 5-dibromophenol (2.0 g, 7.94 mmol) and (2S)-2-[(tert-butyldimethylsilyl)oxy]propyl 4-methylbenzenesulfonate (5.46 g, 15.85 mmol) and Cs₂CO₃ (5.17 g, 15.86 mmol) in DMF (20 mL) was stirred overnight at 100° C. The mixture was allowed to cool down to RT. The resulting mixture was extracted with EA (40 mL×3). The combined organic layers were washed with brine (40 mL×2), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated and purified by combi-flash (EA/PE=3-5%) to give tert-butyl([[(2S)-1-(3,5-dibromophenoxy)propan-2-yl]oxy])dimethylsilane (1.90 g, 56% yield).

Step 4: [[(2S)-1-[3-bromo-5-(methylsulfanyl)phenoxy]propan-2-yl]oxy](tertbutyl)dimethylsilane

A mixture of tert-butyl([[(2S)-1-(3,5-dibromophenoxy)propan-2-yl]oxy])dimethylsilane (2.00 g, 4.72 mmol), (methylsulfanyl)sodium (332.00 mg, 4.74 mmol), DIEA (1.64 mL, 3.48 mmol), Pd₂(dba)₃ (216.00 mg, 0.24 mmol) and Xantphos (274.00 mg, 0.48 mmol) in dioxane (20 mL) was stirred for 4 h at 75° C. under N₂ atmosphere. The mixture was allowed to cool down to RT. The resulting mixture was extracted with EA (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na₂SO₄, concentrated to give the reside and purified by Prep-TLC (PE/EA=20:1) to give [[(2S)-1-[3-bromo-5-(methylsulfanyl)phenoxy]propan-2-yl]oxy](tert-butyl)dimethylsilane (940 mg, 50% yield).

Step 5: [[(2S)-1-(3-bromo-5-methanesulfonylphenoxy)propan-2-yl]oxy](tert-butyl)dimethylsilane

To a stirred solution of [[(2S)-1-[3-bromo-5-(methylsulfanyl)phenoxy]propan-2-yl]oxy](tert-butyl)dimethylsilane (940 mg, 2.40 mmol) in THF (10 mL) were added RuCl₃H₂O (15 mg, 0.08 mmol) and NaIO₄ (1.03 g, 4.80 mmol) in H₂O (10 mL) at 0° C. and the resulting solution was stirred for 1 h at 0° C. The resulting mixture was extracted with EA (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na₂SO₄, concentrated and purified by Prep-TLC (PE/EA=10:1) to give [[(2S)-1-(3-bromo-5-methanesulfonylphenoxy)propan-2-yl]oxy](tert-butyl)dimethyl silane (646.4 mg, 63% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.58 (m, 1H), 7.34 (m, 1H), 7.31 (m, 1H), 4.24-4.12 (m, 1H), 3.89-3.72 (m, 2H), 3.06 (s, 3H), 1.29-1.23 (d, J=8.0 Hz, 3H), 0.91 (s, 9H), 0.10 (s, 6H). LCMS (ESI) m/e [M+1]⁺ 422.

Example BB46: Synthesis of 2-bromo-4-isobutoxy-6-(methylsulfonyl)pyridine

A solution of 2-bromo-6-methanesulfonylpyridin-4-ol (500 mg, 1.98 mmol), isobutyl bromide (815 mg, 5.95 mmol) and K₂CO₃ (548 mg, 3.97 mmol) in DMF (5 mL) was stirred for 2 h at 80° C. The resulting mixture was extracted with EA (100 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EA/PE=1:5) to give 2-bromo-4-isobutoxy-6-(methylsulfonyl)pyridine (547 mg, 89% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.61 (s, 1H), 7.54 (s, 1H), 4.02 (d, J=6.5 Hz, 2H), 3.29 (s, 3H), 2.06-2.02 (m, 1H), 0.98 (d, J=6.7 Hz, 6H). LCMS (ESI) m/e [M+1]⁺ 309.

Example BB48: Synthesis of 2-bromo-3-(difluoromethoxy)-6-(methylsulfonyl)pyridine

Step 1: 2-bromo-3-(difluoromethoxy)-6-iodopyridine

A solution of 2-bromo-6-iodopyridin-3-ol (5.00 g, 16.67 mmol), sodium 2-chloro-2,2-difluoroacetate (5.08 g, 33.34 mmol) and Cs₂CO₃ (10.86 g, 33.34 mmol) in DMF (50 mL) was stirred for 4 h at 80° C. The resulting mixture was extracted with EA (200 mL×3). The combined organic layers were washed with brine (200 mL×3), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give the crude product 2-bromo-3-(difluoromethoxy)-6-iodopyridine (5.00 g) and used in the next step directly without further purification. LCMS (ESI) m/e [M]⁺ 350.

Step 2: 2-bromo-3-(difluoromethoxy)-6-(methylsulfanyl)pyridine

To a solution of 2-bromo-3-(difluoromethoxy)-6-iodopyridine (2.00 g, 5.72 mmol) and CH₃SNa (320 mg, 4.57 mmol) in dioxane (20 mL) were added Xantphos (331 mg, 0.57 mmol) and Pd₂(dba)₃ (523 mg, 0.57 mmol). After stirring for 4 h at 70° C. under a nitrogen atmosphere, the resulting mixture was extracted with EA (200 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated to give the crude product 2-bromo-3-(difluoromethoxy)-6-(methylsulfanyl)pyridine (2.0 g) and used in the next step directly without further purification. LCMS (ESI) m/e [M]⁺ 270.

Step 3: 2-bromo-3-(difluoromethoxy)-6-methanesulfonylpyridine

To a solution of 2-bromo-3-(difluoromethoxy)-6-(methylsulfanyl)pyridine (2.00 g, 7.41 mmol) in THF (20 mL) was added RuCl₃·H₂O (50 mg, 0.22 mmol) at 0° C. NaIO₄ (6.34 g, 29.62 mmol) and H₂O (20 mL) was added and the mixture was allowed to warm to RT and stirred for 1 h. The resulting mixture was extracted with EA (200 mL×3). The combined organic layers were washed with brine (200 mL×3), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EA/PE=1:3) to give 2-bromo-3-(difluoromethoxy)-6-methanesulfonylpyridine (556.8 mg, 25% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (d, J=8.4 Hz, 4H), 8.08-8.01 (m, 1H), 7.71-7.35 (m 1H), 3.32 (s, 3H). LCMS (ESI) m/e [M]⁺ 301.

Example BB49: Synthesis of 5-bromo-7-methanesulfonyl-2H,3H-[1,4]dioxino[2,3-c]pyridine

Step 1: 2-bromo-6-iodo-3-methoxypyridine

A mixture of 2-bromo-6-iodopyridin-3-ol (11.00 g, 36.68 mmol), CH₃I (10.41 g, 73.34 mmol), K₂CO₃ (10.14 g, 73.35 mmol) in DMF (165 mL) was stirred for 1 h at RT. The resulting solution was added to H₂O (200 mL) and extracted with EA (100 mL×3), The combined organic layers were washed with brine (200 mL×3), dried over anhydrous Na₂SO₄, concentrated to give the residue and purified by combi-flash (EA/PE=0-6%) to give 2-bromo-6-iodo-3-methoxypyridine (11.00 g, 85% yield). LCMS (ESI) m/e [M+1]⁺ 314.

Step 2: 2-bromo-6-iodo-3-methoxypyridin-4-ol

Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 2-bromo-6-iodo-3-methoxypyridine (5.00 g, 15.92 mmol), THF (100 mL). This was followed by the addition of LDA (2.0 M, 9.6 mL, 19.11 mmol) dropwise with stirring at −78° C. The resulting solution was stirred for 1 h at −78° C. To the mixture was added trimethyl borate (2.48 g, 23.86 mmol) dropwise with stirring at −78° C. The resulting solution was stirred for 2 h at −78° C. To the mixture was added H₂O₂ (0.15 mL) dropwise with stirring at −60° C. The resulting solution was allowed to react, with stirring, for an additional 1 h at RT. The reaction was then quenched by the addition of Na₂S₂O₃. The resulting solution was extracted with EA (50 mL×3), dried over anhydrous Na₂SO₄, concentrated under reduced pressure to give the residue and purified by combi-flash (EA/PE=0-36%) to give 2-bromo-6-iodo-3-methoxypyridin-4-ol (1.92 g, 32% yield). LCMS (ESI) m/e [M+1]⁺ 330.

Step 3: 2-bromo-6-iodopyridine-3,4-diol

To a solution of 2-bromo-6-iodo-3-methoxypyridin-4-ol (1.92 g, 5.82 mmol) in DCM (35 mL) was followed by the addition of BBr₃ (4.37 g, 17.45 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at rt. The reaction was then quenched by the addition of MeOH (5 mL). The resulting mixture was concentrated under vacuum and purified by combi-flash (EA/PE=0-8%) to give 2-bromo-6-iodopyridine-3,4-diol (2.12 g crude). LCMS (ESI) m/e [M+1]⁺ 316.

Step 4: 5-bromo-7-iodo-2H,3H-[1,4]dioxino[2,3-c] pyridine

A mixture of 2-bromo-6-iodopyridine-3,4-diol (2.12 g, 6.71 mmol), 1,2-dibromoethane (1.89 g, 10.06 mmol), K₂CO₃ (4.64 g, 33.55 mmol) in DMF (40 mL) was stirred for 2 h at 90° C. The resulting solution was added to H₂O (100 mL) and extracted with EA (50 mL×3), dried over anhydrous Na₂SO₄, concentrated to give 5-bromo-7-iodo-2H,3H-[1,4]dioxino[2,3-c] pyridine (1.26 g, 49% yield). LCMS (ESI) m/e [M+1]⁺ 342.

Step 5: 5-bromo-7-(methylsulfanyl)-2H,3H-[1,4]dioxino[2,3-c] pyridine

A mixture of 5-bromo-7-iodo-2H,3H-[1,4]dioxino[2,3-c] pyridine (1.26 g, 3.68 mmol), (methylsulfanyl)sodium (0.23 g, 3.28 mmol), Pd₂(dba)₃ (0.17 g, 0.18 mmol), Xantphos (0.21 g, 0.36 mmol) in dioxane (20 mL) was stirred for 3 h at 75° C. The resulting mixture was filtrated and filtrate was concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-5%) to give 5-bromo-7-(methylsulfanyl)-2H,3H-[1,4]dioxino[2,3-c] pyridine (492 mg, 45% yield). LCMS (ESI) m/e [M+1]⁺ 262.

Step 6: 5-bromo-7-methanesulfonyl-2H,3H-[1,4]dioxino[2,3-c] pyridine

To a solution of 2-bromo-3-[(4-methoxyphenyl)methoxy]-6-(methylsulfanyl)pyridine (492.8 mg, 1.88 mmol) in THF (10 mL) was added RuCl₃·H₂O (12.72 mg, 0.05 mmol) at 0° C. NaIO₄ (1206.4 mg, 5.64 mmol) in H₂O (10 mL) was added at 0° C. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-25%) to give 5-bromo-7-methanesulfonyl-2H,3H-[1,4]dioxino[2,3-c] pyridine (207.0 mg, 33%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.56 (s, 1H), 4.54-4.48 (m, 4H), 3.23 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 294.

Example BB50: Synthesis of (R)-2-bromo-4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridine

Step 1: (R)-2-methoxypropyl 4-methylbenzenesulfonate

To a mixture of NaH (60% in mineral oil, 1.2 g, 30 mmol) in DMF (20 mL) was added 4-(R)-2-methoxypropan-1-ol (1.8 g, 20 mmol) at 0˜ 5° C., after 30 mins, methylbenzenesulfonyl chloride (5.7 g, 30 mmol) was added to the mixture and stirred for 16 h at RT. The mixture was poured into water (50 mL), and extracted with EA (20 mL×3). The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure to give (R)-2-methoxypropyl 4-methylbenzenesulfonate (3.95 g, 82.3%). MS (ESI) m/e [M+1]⁺ 245.

Step 2: (R)-2,6-dibromo-4-(2-methoxypropoxy)pyridine

A mixture of (R)-2-methoxypropyl 4-methylbenzenesulfonate (3.95 g, 16.2 mmol), 2,6-dibromopyridin-4-ol (3.37 g, 13.5 mmol), K₂CO₃ (3.72 g, 27.0 mmol) in DMF (20 mL) was heated to 80° C. 16 h. The mixture was poured into water (50 mL), and extracted with EA (20 mL×3). The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure to give (R)-2,6-dibromo-4-(2-methoxypropoxy)pyridine (3.05 g, 71.3%). MS (ESI) m/e [M+1]⁺ 325.

Step 3: (R)-2-bromo-4-(2-methoxypropoxy)-6-(methylthio)pyridine

A mixture of (R)-2,6-dibromo-4-(2-methoxypropoxy)pyridine (3.0 g, 9.23 mmol), Sodium methyl mercaptan (wt: 20%, 7.9 g, 27.7 mmol) in DMF (20 mL) was stirred for 16 h at RT. The mixture was poured into water (50 mL), and extracted with EA (20 mL×3). The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure to give (R)-2-bromo-4-(2-methoxypropoxy)-6-(methylthio)pyridine (2.4 g, 88.9%). MS (ESI) m/e [M+1]⁺ 292.

Step 4: (R)-2-bromo-4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridine

A mixture of (R)-2-bromo-4-(2-methoxypropoxy)-6-(methylthio)pyridine (2.4 g, 8.22 mmol), 3-Chloroperbenzoic acid (2.12 g, 12.33 mmol) in DCM (30 mL) was stirred for 16 h at RT. The DCM was exchanged by EA (30 mL), then the organic layer was washed with the mixture solution NaHCO₃ (10 mL) and Na₂S₂O₃ (10 mL), dried over Na₂SO₄, concentrated to give the crude product and purification by column chromatograph on silica gel using EA/PE (1/2) as eluant to afford (R)-2-bromo-4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridine (2.5 g, 93.6%). MS (ESI) m/e [M+1]⁺ 324.

Example BB51: Synthesis of 6-bromo-3-methoxy-2-(methylsulfonyl)pyridine

Step 1: 6-bromo-3-methoxy-2-(methylthio)pyridine

Into a 100-mL round-bottom flask, were placed 6-bromo-2-fluoro-3-methoxypyridine (1.00 g, 4.85 mmol), DMF (10 mL), NaSCH₃ (339.78 mg, 4.85 mmol). The resulting solution was stirred for 1 h at RT. The resulting solution was diluted with EA (100 mL). The resulting mixture was washed with H₂O (100 mL×3). The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was purified by combi-flash (EA/PE=0-15%) give the product (0.90 g, 79% yield). LCMS (ESI) m/e [M+1]⁺ 234.

Step 2: 6-bromo-3-methoxy-2-(methylsulfonyl)pyridine

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 6-bromo-3-methoxy-2-(methylsulfanyl)pyridine (1.00 g, 4.27 mmol), THF (10 mL), H₂O (10 mL), NaIO₄ (3.65 g, 17.07 mmol), RuCl₃·H₂O (192.59 mg, 0.85 mmol). The resulting solution was stirred for 1 h at 0° C. The resulting solution was diluted with EA (100 mL). The resulting mixture was washed with H₂O (100 mL×3). The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was purified by combi-flash (EA/PE=0-20%) give the product (705.30 mg, 62% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.66 (d, J=8.7 Hz, 1H), 7.37 (d, J=8.7 Hz, 1H), 4.03 (s, 3H), 3.35 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 266.

Example BB52: Synthesis of 2-bromo-6-(methylsulfonyl)-4-phenylpyridine

Step 1: Synthesis of 2,6-dibromo-4-phenylpyridine

Into a 250 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 2,6-dibromo-4-iodopyridine (5.20 g, 14.33 mmol), dioxane (30 mL), H₂O (10 mL), phenyl boronic acid (1.75 g, 14.35 mmol), Na₂CO₃ (3.04 g, 28.68 mmol), Pd(PPh₃)₄ (1656.31 mg, 1.43 mmol). The resulting solution was stirred for 2 h at 90° C. The resulting solution was diluted with (100 mL). The resulting mixture was washed with H₂O (100 mL×3). The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was purified by combi-flash (EA/PE=0-15%) give the product (0.77 g, 17% yield). LCMS (ESI) m/e [M+1]⁺ 312.

Step 2: 2,6-dibromo-4-phenylpyridine

Into a 100 mL round-bottom flask, were placed 2,6-dibromo-4-phenylpyridine (770.00 mg, 2.460 mmol), DMF (10 mL, NaSCH₃ (172.21 mg, 2.46 mmol). The resulting solution was stirred for 1 h at rt. The resulting solution was diluted with EA (100 mL). The resulting mixture was washed with H₂O (100 mL×3). The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was purified by combi-flash (EA/PE=0-10%) give the product (0.43 g, 62% yield). LCMS (ESI) m/e [M+1]⁺ 280.

Step 3: 2-bromo-6-(methylsulfonyl)-4-phenylpyridine

Into a 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 2-bromo-6-(methylsulfanyl)-4-phenylpyridine (430.00 mg, 1.54 mmol), THF (10 mL), H₂O (10 mL), NaIO₄ (1313.06 mg, 6.14 mmol), RuCl₃·H₂O (69.20 mg, 0.31 mmol). The resulting solution was stirred for 1 h at 0° C. The resulting solution was diluted with EA (50 mL). The resulting mixture was washed with H₂O (50 mL×3). The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was purified by combi-flash (EA/PE=0-25%) give the product (386.50 mg, 80% yield). 1H NMR (400 MHz, DMSO-d₆) δ 8.37 (d, J=1.5 Hz, 1H), 8.29 (d, J=1.5 Hz, 1H), 8.01-7.92 (m, 2H), 7.63-7.54 (m, 3H), 3.37 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 312.

Example BB53: Synthesis of 2-bromo-4-methyl-6-(methylsulfonyl)pyridine

Step 1: 2-bromo-4-methyl-6-(methylthio)pyridine

Into a 250-mL round-bottom flask, were placed 2,6-dibromo-4-methylpyridine (4.00 g, 15.62 mmol), DMF (50 mL), NaSCH₃ (0.98 g, 14.00 mmol). The resulting solution was stirred for 3 h at 25° C. The resulting solution was diluted with H₂O (100 mL), extracted with 3×80 mL of EA (100 mL×3) and the organic layers were combined and concentrated. The residue was purified by combi-flash (EA/PE=0-20%) to give the product (3.3 g, 87% yield). LCMS (ESI, m/z) [M+1]⁺ 218.

Step 2: 2-bromo-4-methyl-6-(methylsulfonyl)pyridine

Into a 250-mL round-bottom flask, were placed 2-bromo-4-methyl-6-(methylsulfanyl)pyridine (3.30 g, 13.61 mmol), THF (30 mL), H₂O (10 mL). This was followed by the addition of NaIO₄ (11.65 g, 0.05 mmol) in H₂O (10 mL) in portions at 0° C. To the mixture was added RuCl₃ (0.31 g, 1.37 mmol) in H₂O (10 mL) in portions at 0° C. The resulting solution was stirred for 1 h at 25° C. The resulting solution was diluted with H₂O, extracted with EA (100 mL×3) and the organic layers were combined and concentrated. The residue was purified by combi-flash (EA/PE=0-30%) to give the product (2.45 g, 65% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 7.97 (t, J=0.9 Hz, 1H), 7.92 (t, J=1.1 Hz, 1H), 3.30 (s, 3H), 2.47 (s, 3H). LCMS (ESI, m/z): [M+H]⁺ 250.

Example BB54: Synthesis of 2-bromo-6-methanesulfonyl-4-phenoxypyridine

Step 1: 2,6-dibromo-4-phenoxypyridine

Into a 250-mL round-bottom flask, were placed 2,6-dibromo-4-chloropyridine (4.80 g, 17.69 mmol), DMF (75 mL), phenol (1.50 g, 15.93 mmol), Cs₂CO₃ (11.53 g, 35.38 mmol). The resulting solution was stirred for 2 h at 90° C. in an oil bath. The resulting solution was extracted with EA (50 mL×3) concentrated. The residue was purified by prep-MPLC (column: C18 spherical 20-35 um, 100A, 330 g; phase: A-H₂O (0.05% TFA); B-Acetonitrile, B %: 60%-70% in 40 min) to give the product (0.96 g, 14% yield). LCMS (ESI) m/e [M+1]⁺ 330.

Step 2:2-bromo-6-(methylsulfanyl)-4-phenoxypyridine

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 2,6-dibromo-4-phenoxypyridine (0.96 g, 2.91 mmol), dioxane (15 mL), (methylsulfanyl)sodium (0.18 g, 2.56 mmol), Pd₂(dba)₃ (0.13 g, 0.14 mmol), XantPhos (0.17 g, 0.29 mmol). The resulting solution was stirred for 3 h at 75° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-1%) to give the product (0.82 g, 85%). LCMS (ESI) m/e [M+1]⁺ 296.

Step 3: 2-bromo-6-methanesulfonyl-4-phenoxypyridine

Into a 25-mL round-bottom flask, were placed 2-bromo-6-(methylsulfanyl)-4-phenoxypyridine (0.82 g, 2.76 mmol), THF (7 mL). This was followed by the addition of NaIO₄ (1.78 g, 8.32 mmol) and RuCl₃ (0.020 g, 0.080 mmol) in H₂O (7 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-11%) to give the product (488.80 mg, 48% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 7.60-7.51 (m, 3H), 7.43-7.36 (m, 2H), 7.34-7.27 (m, 2H), 3.28 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 328.

Example BB55: Synthesis of 2-chloro-6-methanesulfonyl-4-(trifluoromethyl)pyridine

Step 1: 2-chloro-6-(methylsulfanyl)-4-(trifluoromethyl)pyridine

Into a 250-mL round-bottom flask, were placed 2,6-dichloro-4-(trifluoromethyl) pyridine (6.00 g, 27.78 mmol), DMF (90.00 mL), (methylsulfanyl)sodium (1.75 g, 24.97 mmol). The resulting solution was stirred for 1 h at RT. The resulting solution was extracted with 3×50 mL of EA concentrated. The residue was purified by combi-flash to give the product (2.56 g, 36% yield). GCMS (ESI) m/e [M] 227.

Step 2: 2-chloro-6-methanesulfonyl-4-(trifluoromethyl)pyridine

Into a 100-mL 3-necked round-bottom flask, were placed 2-chloro-6-(methylsulfanyl)-4-(trifluoromethyl) pyridine (2.56 g, 11.24 mmol), THF (20 mL). This was followed by the addition of NaIO₄ (7.22 g, 33.75 mmol) and RuCl₃ (0.08 g, 0.337 mmol) in H₂O (20 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EA/PE=0-11%) to give the product (1.08 g, 33% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.49-8.46 (m, 1H), 8.35-8.30 (m, 1H), 3.38 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 260.

Example BB56: Synthesis of 6-bromo-3-methyl-2-(methylsulfonyl)pyridine

Step: 1:6-bromo-2-fluoro-3-methylpyridine

Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 2-bromo-6-fluoropyridine (10.00 g, 56.82 mmol), THF (200 mL). This was followed by the addition of LDA (7.91 g, 73.87 mmol) dropwise with stirring at −78° C. in 15 mins. The resulting solution was stirred for 3 h at −78° C. in a liquid nitrogen bath. To this was added methyl iodide (8.87 g, 62.50 mmol) dropwise with stirring at −78° C. in 5 min. The resulting solution was allowed to react, with stirring, for an additional 1 h at RT. The reaction was then quenched by the addition of aq. NH₄Cl (150 mL). The resulting solution was extracted with EA (100 mL×3). The resulting mixture was washed with H₂O. The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (PE/EA=0-10%) give the product (4.4 g, 40% yield). LCMS (ESI) m/e [M+1]⁺ 190.

Step: 2: 6-bromo-3-methyl-2-(methylthio)pyridine

Into a 100-mL round-bottom flask, were placed 6-bromo-2-fluoro-3-methylpyridine (3.40 g, 17.89 mmol), DMF (40 mL), NaSCH₃ (1.00 g, 14.31 mmol). The resulting solution was stirred for 1.5 h at RT. The reaction was then quenched by the addition of aq. NH₄Cl (50 mL). The resulting solution was extracted with EA (50 mL×3). The resulting mixture was washed with H₂O. The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (PE/EA=0-1%) give the product (2.9 g, 74% yield). LCMS (ESI) m/e [M+1]⁺ 218.

Step: 3: 6-bromo-3-methyl-2-(methylsulfonyl)pyridine

Into a 250-mL round-bottom flask, were placed 6-bromo-3-methyl-2-(methylsulfanyl)pyridine (2.90 g, 13.29 mmol), THF (30 mL). This were followed by the addition of NaIO₄ (8.53 g, 39.88 mmol), H₂O (30 mL) and RuCl₃ (82.57 mg, 0.40 mmol), in portions at 0° C. in 5 min. The resulting solution was stirred for 1 h at RT. The resulting solution was extracted with 50 mL of EA. The resulting mixture was washed with H₂O (25 mL×2). The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (PE/EA=0-13%) give the product (2.48 g, 75% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.93-7.89 (m, 2H), 3.38 (s, 3H), 2.57 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 250.

Example BB57: Synthesis of 2-bromo-6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridine

Step 1: Synthesis of 2,6-dibromo-4-iodopyridine

In a flame-dried and nitrogen-flushed 3-necked Schlenk tube equipped with a rubber septum and a magnetic stirring bar, 2,6-dibromopyridine (5.0 g, 21.11 mmol) was dissolved in dry THF (20 mL). The mixture was cooled to −30° C. Then 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex (32 mL, 31.70 mmol, 1 M in THF) was added dropwise via a syringe and stirred for a further 30 min at that temperature. Then 1₂ (5.9 g, 23.24 mmol) was added quickly to the mixture at −30° C. under the protection of nitrogen gas and stirred for 30 min at the same temperature. The reaction mixture was quenched by adding 30 mL of sat. NH₄Cl followed by extraction with EtOAc, dryness over anhydrous Na₂SO₄ and concentration under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (1/10, v/v) to afford the product (3.0 g, 39% yield). LCMS (ESI) m/e [M+1]⁺=362.

Step 2: Synthesis of 2,6-dibromo-4-(3,6-dihydro-2H-pyran-4-yl)pyridine

Into a stirred solution of 2,6-dibromo-4-iodopyridine (2.0 g, 5.51 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 g, 5.71 mmol) in 1,4-dioxane (40 mL) and water (8 mL), were added Pd(dppf)Cl₂ (403 mg, 0.55 mmol) and K₂CO₃ (1.5 g, 10.85 mmol) at it under nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 90° C. under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL) and then dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (1/12, v/v) to give the product (1.2 g, 68% yield). LCMS (ESI) m/e [M+1]=318.

Step 3: Synthesis of 2,6-dibromo-4-(tetrahydro-2H-pyran-4-yl)pyridine

Into a solution of 2,6-dibromo-4-(3,6-dihydro-2H-pyran-4-yl)pyridine (1.0 g, 3.13 mmol) in EtOAc (30 mL) was added 5% Rh/C (200 mg, 5% wt). The mixture was stirred at room temperature overnight under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to afford the product (1.0 g, 100% yield). LCMS (ESI) m/e [M+1]⁺=320.

Step 4: Synthesis of 2-bromo-6-(methylthio)-4-(tetrahydro-2H-pyran-4-yl)pyridine

A solution of 2,6-dibromo-4-(tetrahydro-2H-pyran-4-yl)pyridine (1.0 g, 3.11 mmol) and Sodium thiomethoxide (195 mg, 2.79 mmol) in DMF (10 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (1/4, v/v) to give the product (550 mg, 61% yield) LCMS (ESI) m/e [M+1]⁺=288.

Step 5: Synthesis of 2-bromo-6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridine

To a stirred solution of 2-bromo-6-(methylthio)-4-(tetrahydro-2H-pyran-4-yl)pyridine (550 mg, 1.91 mmol) in water (5 mL) and THF (5 mL) was added RuCl₃·H₂O (12 mg, 0.05 mmol) in water (2 mL) dropwise at 0° C. To the above mixture was added NaIO₄ (1.5 g, 7.01 mmol) in water (10 mL) dropwise at 0° C. The resulting mixture was stirred for additional 30 min at 0° C. The resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc:PE=1:5) to give the product (361 mg, 59% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 7.97 (s, 1H), 7.95 (s, 1H), 3.97-3.94 (m, 2H), 3.44-3.39 (m, 2H), 3.33 (s, 3H), 3.08-3.00 (m, 1H), 1.78-1.69 (m, 4H). LCMS (ESI) m/e [M+1]⁺=320.

Example BB58: Synthesis of 2-bromo-3,4-dimethoxy-6-(methylsulfonyl)pyridine

Step: 1:2-bromo-6-iodo-3,4-dimethoxypyridine

Into a 250-mL round-bottom flask, were placed 2-bromo-6-iodo-3-methoxypyridin-4-ol (2.95 g, 8.94 mmol), DMF (90 mL) and K₂CO₃ (2.47 g, 17.88 mmol). This was followed by the addition of CH₃I (2.54 g, 17.88 mmol) at 0° C. in 5 mins. The resulting solution was stirred for 1 hr at rt. The reaction was then quenched by the addition of 40 mL of NH₄Cl (aq). The resulting solution was extracted with of EtOAc (40 mL×2) and combined organic layer was washed with H₂O and brine. The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (PE/EtOAc=0-11%) to give the product (2.6 g, 84.5% yield). LCMS (ESI) m/e [M+1]⁺ 344.

Step: 2: 2-bromo-3,4-dimethoxy-6-(methylthio)pyridine

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 2-bromo-6-iodo-3,4-dimethoxypyridine (2.60 g, 7.56 mmol), Pd₂(dba)₃ (346.1 mg, 0.38 mmol), Xant-phos (437.4 mg, 0.76 mmol) and dioxane (60 mL). This was followed by the addition of CH₃SNa (529.6 mg, 7.56 mmol). The resulting solution was stirred overnight at 75° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (PE/EtOAc=0-6%) to give the product (1.64 g, 82%). LCMS (ESI) m/e [M+1]⁺ 264.

Step: 3: 2-bromo-3,4-dimethoxy-6-(methylsulfonyl)pyridine

Into a 100-mL round-bottom flask, were placed 2-bromo-3,4-dimethoxy-6-(methylsulfanyl)pyridine (1.60 g, 6.06 mmol), H₂O (35 mL), THF (35 mL). This was followed by the addition of RuCl₃ (126 mg, 0.61 mmol) at 0° C. in 2 min. To this was added NaIO₄ (3.89 g, 18.17 mmol) at 0° C. in 2 min. The resulting solution was stirred for 1 RT at rt. The reaction was then quenched by the addition of 50 mL of NH₄Cl (aq). The resulting solution was extracted with EtOAc (80 mL) and the combined organic layer was washed with brine. The resulting mixture was concentrated under vacuum and the residue was purified by combi-flash (PE/EtOAc=0-18%) to give the product (354.5 mg, 19.8%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.72 (s, 1H), 4.06 (s, 3H), 3.88 (s, 3H), 3.28 (s, 3H). LCMS (ESI) m/e [M+1]⁺ 296.

Example BB59: Synthesis of 2-bromo-4-(methoxy-d3)-6-(methylsulfonyl)pyridine

Step 1: 2,6-dibromo-4-(methoxy-d3)pyridine

A mixture of 2,6-dibromopyridin-4-ol (2.4 g, 9.5 mmol), CD₃I (1.4 g, 9.5 mmol), K₂CO₃ (3.9 g, 28.5 mmol) in DMF (30 mL) was stirred at 25° C. for 2 hr. Upon completion of the reaction, H₂O (200 mL) was added and the resulting solution was extracted with EA (30 mL×3). The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo to give the crude product (2.56 g, crude). MS(ESI) m/e [M+1]⁺ 269.

Step 2: 2-bromo-4-(methoxy-d3)-6-(methylthio)pyridine

To a solution of 2,6-dibromo-4-(methoxy-d3)pyridine (2.56 g, 9.5 mmol) in DMF (30 ml) was added NaSMe (731 mg, 10.4 mmol) in one portion at 25° C. The mixture was stirred at 25° C. for 16 h. The mixture was poured into H₂O (200 ml) and extracted with EA (30 mL×3). The combined organic layers were dried over Na₂SO₄ and concentrated to give crude product (2.4 g, crude). MS(ESI) m/e [M+1]⁺ 237.

Step 3: 2-bromo-4-(methoxy-d3)-6-(methylsulfonyl)pyridine

To a solution of 2-bromo-4-(methoxy-d3)-6-(methylthio)pyridine (2.4 g, 10.1 mmol) in MeOH (40 ml)/H₂O (20 ml) was added Oxone (12.4 g, 20.1 mmol) at 25° C. The mixture was stirred at RT for 2 hr. Upon completion of the reaction, the solid was filtered out and the filtrate was concentrated. The crude product was purified by silica gel column chromatography eluted with (PE/EtOAc 100:1 to 20:1) to give the product (1.3 g, 47% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.57 (s, 1H), 7.18 (s, 1H), 3.25 (s, 3H). MS(ESI) m/e [M+1]⁺ 269.

Example BB60: Synthesis of (R and S)-2-chloro-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine

Step 1. Synthesis of 1-(2,6-dichloropyridin-4-yl)ethan-1-ol

To a stirred solution of 2,6-dichloro-4-iodopyridine (10.00 g, 36.51 mmol) in THF (100 mL) was added n-BuLi in n-hexane (21.9 mL, 2.5 M, 54.77 mmol) dropwise at −78° C. under N₂ atmosphere. The resulting mixture was stirred for 1 h at −78° C. To the above mixture was added acetaldehyde (4.83 g, 0.11 mmol) dropwise over 15 min at −78° C. The resulting mixture was stirred for additional 1 h at −78° C. The reaction was quenched with sat. NH₄Cl (aq.) at −78° C. The resulting mixture was extracted with EtOAc (2×300 mL). The combined organic layers were washed with brine (2×200 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product (5.50 g, 78% yield) was used in the next step directly without further purification. LCMS (ESI) m/e [M+1]191.99.

Step 2. Synthesis of 2,6-dichloro-4-(1-methoxyethyl)pyridine

To a stirred solution of 1-(2,6-dichloropyridin-4-yl)ethanol (5.50 g, 28.64 mmol) and CH₃I (6.10 g, 42.98 mmol) in THF (100 mL) were added NaH (1.37 g, 60% in mineral oil, 57.28 mmol) in portions at 0° C. The resulting mixture was stirred for 2 h at rt under N₂ atmosphere. The reaction was quenched with Water/Ice at 0° C. The resulting mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (1×200 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product (5 g, crude) was used in the next step directly without further purification. LCMS (ESI) m/e [M+1]⁺ 206.

Step 3. Synthesis of 2-chloro-4-(1-methoxyethyl)-6-(methylthio)pyridine

To a stirred solution of 2,6-dichloro-4-(1-methoxyethyl)pyridine (5.00 g, 24.26 mmol) in DMF (50 mL) was added MeSNa (2.55 g, 36.43 mmol) in portions at 0° C. The resulting mixture was stirred for 3 h at rt. The resulting mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (2×200 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product (7 g, crude) was used in the next step directly without further purification. LCMS (ESI) m/e [M+1]⁺ 218.

Step 4. Synthesis of 2-chloro-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine

To a stirred solution of 2-chloro-4-(1-methoxyethyl)-6-(methylsulfanyl)pyridine (7.00 g, 32.15 mmol) and RuCl₃·H₂O (0.22 g, 0.97 mmol) in THF (70 mL) and H₂O (70 mL) were added NaIO₄ (13.75 g, 64.29 mmol) in portions at 0° C. and the resulting mixture was stirred at rt for 10 h. The resulting mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (2×200 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (PE/EtOAc=0-20%) to give the product (5 g, 62%). LCMS (ESI) m/e [M+1]⁺ 250.

Step 5. Synthesis of (R and S)-2-chloro-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine

Racemic 2-chloro-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine) (3 g) was separated by chiral-HPLC with the following conditions (Column: CHIRAL ART Cellulose-SB, 5×25 cm, 5 um; Mobile Phase A: Hex (0.5% 2M NH₃-MeOH), Mobile Phase B: EtOH; Flow rate: 95 mL/min; Gradient: 20% B to 20% B in 15 min; 220 nm; RTL: 8.55 min; RT2: 9.50 min), the faster peak was collected and concentrated to give one pure isomer (1.32 g, 44% yield). For faster peak (retention time: 8.55 min): ¹H NMR (400 MHz, CDCl₃) δ 7.96 (dd, J=1.3 Hz, 1H), 7.56 (dd, J=1.3 Hz, 1H), 4.43-4.38 (m, 1H), 3.35 (s, 3H), 3.29 (s, 3H), 1.47 (d, J=6.6 Hz, 3H). LCMS (ESI) m/e [M+1]⁺=249.85. The slower peak was collected and concentrated to afford the product (1.22 g, 41% yield). For slower peak (retention time: 9.50 min): ¹H NMR (400 MHz, CDCl₃) δ 7.96 (dd, J=1.2, Hz, 1H), 7.56 (dd, J=1.3 Hz, 1H), 4.46-4.36 (m, 1H), 3.35 (s, 3H), 3.29 (s, 3H), 1.47 (d, J=6.5 Hz, 3H). LCMS (ESI) m/e [M+1]⁺ 250.

Example BB61: Synthesis of (S)-4-(2-chloro-6-(methylsulfonyl)pyridin-4-yl)-3-methylmorpholine

Step 1: Synthesis of (S)-4-(2,6-dichloropyridin-4-yl)-3-methylmorpholine

Into a 250 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 2,6-dichloro-4-iodopyridine (5.00 g, 18.25 mmol), dioxane (100 mL), (3S)-3-methylmorpholine (1.85 g, 18.29 mmol), Pd₂(dba)₃·CHCl₃ (1.89 g, 1.82 mmol), XantPhos (2.11 g, 3.64 mmol) and Cs₂CO₃ (17.84 g, 54.75 mmol). The resulting solution was stirred for 3 hr at 110° C. in an oil bath. After cooling to room temperature, the reaction was concentrated. The residue was purified by combi-flash (EtOAc/PE=0-15%) to give the product (1.20 g, 24%). LCMS (ESI, m/z): [M+H]⁺ 247.

Step 2: Synthesis of (S)-4-(2-chloro-6-(methylthio)pyridin-4-yl)-3-methylmorpholine

Into a 100 mL round-bottom flask, were placed (3S)-4-(2,6-dichloropyridin-4-yl)-3-methylmorpholine (1.90 g, 7.68 mmol), DMF (30 mL) and CH₃SNa (1.08 g, 15.42 mmol). The resulting solution was stirred for 5 hr at 25° C. The resulting solution was diluted with 50 mL of H₂O, extracted with 3×30 mL of EtOAc and the organic layers were combined and concentrated. The residue was purified by combi-flash (EtOAc/PE=0-10%) to give the product (1.40 g, 63%). LCMS (ESI, m/z): [M+H]⁺ 259.

Step 3: Synthesis of (S)-4-(2-chloro-6-(methylsulfonyl)pyridin-4-yl)-3-methylmorpholine

Into a 100 mL round-bottom flask, were placed (3S)-4-[2-chloro-6-(methylsulfanyl)pyridin-4-yl]-3-methylmorpholine (1.40 g, 5.41 mmol), THF (20 mL), H₂O (20 mL), NaIO₄ (4.63 g, 21.64 mmol). To the mixture was added RuCl₃·H₂O (0.12 g, 0.53 mmol) in portions at 0° C. The resulting solution was stirred for 3 hr at 25° C. The resulting solution was diluted with 50 mL of H₂O, extracted with 3×30 mL of ethyl acetate and the organic layers were combined and concentrated. The residue was purified by combi-flash (EtOAc/PE=0-45%) to give the product (1.30 g, 79%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.31 (d, J=2.3 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H), 4.17 (d, J=7.2 Hz, 1H), 4.02-3.90 (m, 1H), 3.81-3.58 (m, 3H), 3.58-3.45 (m, 1H), 3.24-3.15 (m, 4H), 1.18 (d, J=6.7 Hz, 3H). LCMS (ESI, m/z): [M+H]⁺ 291.

Example BB62: Synthesis of (R)-4-(2-chloro-6-(methylsulfonyl)pyridin-4-yl)-3-methylmorpholine

Step 1: Synthesis of (R)-4-(2,6-dichloropyridin-4-yl)-3-methylmorpholine

Into a 250 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 2,6-dichloro-4-iodopyridine (2.50 g, 9.13 mmol), dioxane (50 mL), (3R)-3-methylmorpholine (0.97 g, 9.13 mmol), Pd₂(dba)₃-CHCl₃ (0.97 g, 0.91 mmol), XantPhos (1.06 g, 1.82 mmol), Cs₂CO₃ (8.92 g, 27.38 mmol). The resulting solution was stirred for 3 hr at 110° C. in an oil bath. After cooling to room temperature, the reaction was concentrated and the residue was purified by combi-flash (EtOAc/PE=0-15%) to give the product (1.9 g, 84%). LCMS (ESI, m/z): [M+H]⁺ 247.

Step 2: Synthesis of (R)-4-(2-chloro-6-(methylthio)pyridin-4-yl)-3-methylmorpholine

Into a 100 mL round-bottom flask, were placed (3R)-4-(2,6-dichloropyridin-4-yl)-3-methylmorpholine (1.90 g, 7.68 mmol), DMF (30 mL), CH₃SNa (1.08 g, 15.42 mmol). The resulting solution was stirred for 5 h at 25° C. The resulting solution was diluted with 50 mL of H₂O, extracted with 3×30 mL of ethyl acetate and the organic layers were combined and concentrated. The residue was purified by combi-flash (EtOAc/PE=0-10%) to give the product (1.70 g, 86%). LCMS (ESI, m/z): [M+H]⁺ 259.

Step 3: Synthesis of (R)-4-(2-chloro-6-(methylsulfonyl)pyridin-4-yl)-3-methylmorpholine

Into a 100 mL round-bottom flask, were placed (3R)-4-[2-chloro-6-(methylsulfanyl)pyridin-4-yl]-3-methylmorpholine (1.70 g, 6.59 mmol), THF (20 mL), H₂O (20 mL), NaIO₄ (5.64 g, 26.36 mmol). To the mixture was added RuCl₃—H₂O (0.17 g, 0.66 mmol) in portions at 0° C. The resulting solution was stirred for 3 h at 25° C. The resulting solution was diluted with 50 mL of H₂O, extracted with 3×30 mL of ethyl acetate and the organic layers were combined and concentrated. The residue was purified by combi-flash (EtOAc/PE=0-45%) to give the product (1.20 g, 63%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.30 (d, J=2.3 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 4.16 (d, J=7.2 Hz, 1H), 4.05-3.93 (m, 1H), 3.82-3.56 (m, 3H), 3.57-3.45 (m, 1H), 3.23-3.15 (m, 4H), 1.19 (d, J=6.7 Hz, 3H). LCMS (ESI, m/z): [M+H]⁺ 291.

Example BB63: Synthesis of 2-chloro-6-methanesulfonyl-4-(3-methoxyazetidin-1-yl)pyridine

Step 1: Synthesis of 2,6-dichloro-4-(3-methoxyazetidin-1-yl)pyridine

To a stirred mixture of 2,6-dichloro-4-iodopyridine (3.0 g, 10.95 mmol), 3-methoxyazetidine (1.15 g, 13.14 mmol), Xantphos (633.80 mg, 1.09 mmol) and Cs₂CO₃ (7.14 g, 21.91 mmol) in 1,4-dioxane (30 mL) was added Pd₂(dba)₃ (501.53 mg, 0.55 mmol) at rt. The resulting mixture was stirred for 2 h at 100° C. under N₂ atmosphere. The mixture was allowed to cool down to it. The resulting mixture was extracted with EtOAc (2×50 mL) and the combined organic layers were dried over anhydrous Na₂SO₄. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (EtOAc/PE=20%) to give the product (1.2 g, 47% yield). LCMS (ESI) m/e [M+1]⁺=233.

Step 2: Synthesis of 2-chloro-4-(3-methoxyazetidin-1-yl)-6-(methylsulfanyl)pyridine

To a stirred solution of 2,6-dichloro-4-(3-methoxyazetidin-1-yl)pyridine (1.2 g, 5.15 mmol) in DMF (10 mL) was added CH₃SNa (900.94 mg, 12.87 mmol) at 0° C. The resulting mixture was stirred for 2 h at rt. Upon completion of the reaction, water was added and the resulting mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (2×50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give the crude product (1.2 g). It was used in the next step directly without further purification. LCMS (ESI) m/e [M+1]⁺=245.

Step 3: Synthesis of 2-chloro-6-methanesulfonyl-4-(3-methoxyazetidin-1-yl)pyridine

To a stirred solution of 2-chloro-4-(3-methoxyazetidin-1-yl)-6-(methylsulfanyl)pyridine (1.2 g, 4.90 mmol) and RuCl₃·H₂O (33.16 mg, 0.15 mmol) in THF (10 mL) and H₂O (10 mL) was added NaIO₄ (2.1 g, 9.81 mmol) at 0° C. the mixture was stirred for 1 h at rt. The resulting mixture was extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (EtOAc/PE=50%) to give the product (806.4 mg, 59% yield). ¹H NMR (300 MHz, Chloroform-d) δ 6.96 (s, 1H), 6.35 (s, 1H), 4.48-4.37 (m, 1H), 4.30-4.20 (m, 2H), 3.99-3.90 (m, 2H), 3.38 (s, 3H), 3.21 (s, 3H). LCMS (ESI) m/e [M+1]⁺=277.

Example BB64: Synthesis of 2-chloro-6-methanesulfonyl-4-(4-methoxypiperidin-1-yl)pyridine

Step 1: Synthesis of 2,6-dichloro-4-(4-methoxypiperidin-1-yl)pyridine

To a stirred mixture of 2,6-dichloro-4-iodopyridine (3.0 g, 10.95 mmol), 4-methoxypiperidine (1.51 g, 13.14 mmol), Xantphos (633.80 mg, 1.09 mmol) and Cs₂CO₃ (7.14 g, 21.91 mmol) in 1,4-dioxane (30 mL) was added Pd₂(dba)₃ (501.53 mg, 0.55 mmol) at rt. The resulting mixture was stirred for 3 h at 100° C. under N₂ atmosphere. After cooled to rt, the resulting mixture was extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (EtOAc/PE=25%) to give the product (1.3 g, 45% yield). LCMS (ESI) m/e [M+1]⁺=261.

Step 2: Synthesis of 2-chloro-4-(4-methoxypiperidin-1-yl)-6-(methylsulfanyl)pyridine

To a stirred solution of 2,6-dichloro-4-(4-methoxypiperidin-1-yl)pyridine (1.3 g, 4.98 mmol) in DMF (10 mL) was added CH₃SNa (522.69 mg, 7.47 mmol) at 0° C. The resulting mixture was stirred for 2 h at rt. Water was added and the resulting mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (2×50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. It was used in the next step directly without further purification. LCMS (ESI) m/e [M+1]⁺=273.

Step 3: Synthesis of 2-chloro-6-methanesulfonyl-4-(4-methoxypiperidin-1-yl)pyridine

To a stirred solution of 2-chloro-4-(4-methoxypiperidin-1-yl)-6-(methylsulfanyl)pyridine (1.48 g, 5.42 mmol) and RuCl₃·H₂O (36.69 mg, 0.16 mmol) in THF (15 mL) and H₂O (15 mL) was added NaIO₄ (2.32 g, 10.85 mmol) at 0° C. The resulting mixture was stirred for 1 h at rt. Upon completion of the reaction, the resulting mixture was extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (EtOAc/PE=50%) to give the product (613 mg, 37% yield). ¹H NMR (400 MHz, Chloroform-d) δ 7.36 (s, 1H), 6.75 (s, 1H), 3.70-3.62 (m, 2H), 3.59-3.50 (m, 1H), 3.40 (s, 3H), 3.40-3.31 (m, 2H), 3.22 (s, 3H), 1.98-1.88 (m, 2H), 1.84-1.69 (m, 2H). LCMS (ESI) m/e [M+1]⁺=305.

Example BB65: Synthesis of 2-chloro-4-(1,4-dioxan-2-yl)-6-methanesulfonylpyridine, R or S 2-chloro-4-(1,4-dioxan-2-yl)-6-methanesulfonylpyridine

Step 1: Synthesis of 2,6-dichloro-4-ethenylpyridine

Into a 1000-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 2,6-dichloro-4-iodopyridine (20.00 g, 73.02 mmol), dioxane (200 mL), H₂O (100 mL), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.50 g, 87.65 mmol), Pd(dppf)Cl₂ (5.34 g, 7.30 mmol) and CsF (33.28 g, 219.07 mmol). The resulting solution was stirred for 2 h at 90° C. The resulting solution was extracted with EtOAc (200 mL×3). The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EtOAc/PE=0.1%) to give the product (10.90 g, 86%). LCMS (ESI) m/e [M+1]⁺=174.

Step 2: Synthesis of 1-(2,6-dichloropyridin-4-yl) ethane-1,2-diol

Into a 500-mL round-bottom flask, were placed 2,6-dichloro-4-ethenylpyridine (10.90 g, 62.63 mmol), acetone (110 mL), H₂O (55 mL), NMO (8.07 g, 68.90 mmol) and OSO₄ (7.95 mL, 1 g/mL, 313.20 mmol). The resulting solution was stirred for 4 h at rt. The reaction was then quenched by the addition of 500 mg of florisil. The resulting solution was extracted with EtOAc (3×100 mL). The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EtOAc/PE=32%) to give the product (3.20 g, 24.56%). LCMS (ESI) m/e [M+1]⁺=208.

Step 3: Synthesis of 2,6-dichloro-4-(1,4-dioxan-2-yl) pyridine

Into a 1000-mL round-bottom flask, were placed 1-(2,6-dichloropyridin-4-yl) ethane-1,2-diol (3.00 g, 14.42 mmol), ethylene dichloride (250 mL) and TBAB (1.29 g, 4.00 mmol). This was followed by the addition of NaOH (1 M aq., 50 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 48 h at 35° C. in an oil bath. The resulting solution was extracted with EtOAc (3×150 mL). The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EtOAc/PE=7.90%) to give the product (1.45 g, 43%). LCMS (ESI) m/e [M+1]⁺=234.

Step 4: Synthesis of 2-chloro-4-(1,4-dioxan-2-yl)-6-(methylsulfanyl)pyridine

A mixture of 2,6-dichloro-4-(1,4-dioxan-2-yl) pyridine (1.45 g, 6.19 mmol), DMF (17 mL) and (methylsulfanyl)sodium (0.52 g, 7.42 mmol) was stirred for overnight at rt. Water was added and the resulting solution was extracted with EtOAc (3×50 mL). The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EtOAc/PE=0.6%-5.3%) to give the product (1.48 g, 97%). LCMS (ESI) m/e [M+1]⁺=246.

Step 5: Synthesis of 2-chloro-4-(1,4-dioxan-2-yl)-6-(methylsulfonyl)pyridine and (R or S)-2-chloro-4-(1,4-dioxan-2-yl)-6-(methylsulfonyl)pyridine

Into a 100-mL 3-necked round-bottom flask, were placed 2-chloro-4-(1,4-dioxan-2-yl)-6-(methylsulfanyl)pyridine (1.48 g, 6.02 mmol), THF (12 mL) and H₂O (12 mL). This was followed by the addition of NaIO₄ (3.86 g, 18.06 mmol) in portions with stirring at 0° C. To this was added RuCl₃H₂O (0.20 g, 0.90 mmol) with stirring at 0° C. The resulting solution was stirred for 1 h at rt. The resulting solution was extracted with EtOAc (3×50 mL) and the combined organic layer was concentrated under vacuum. The residue was purified by combi-flash (EtOAc/PE=15-22%) to give the racemic product (1.10 g). The racemic product was purified by Prep-SFC with the following conditions (Column: CHIRALPAK AD-3, 3.0×50 mm, 3 m; Mobile Phase B: MeOH (0.1% DEA); Flow rate: 2 mL/min; Gradient: isocratic 10% B; Wave Length: 220 nm) to give the product.

First peak (434.90 mg, 26.00%, RT₁: 0.959 min): ¹H NMR (300 MHz, DMSO-d₆) δ 8.06 (s, 1H), 7.90 (s, 1H), 4.86-4.83 (m, 1H), 4.15-3.92 (m, 2H), 3.87-3.73 (m, 2H), 3.61-3.59 (m, 1H), 3.33 (s, 4H). LCMS (ESI) m/e [M+1]⁺=278.

Second peak (413.3 mg, 24.71%, RT₂: 1.605 min): ¹H NMR (300 MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.89 (s, 1H), 4.85-4.82 (m, J=9.9 Hz, 1H), 4.14-3.92 (m, 2H), 3.86-3.73 (m, 2H), 3.60-3.57 (m, 1H), 3.33-3.25 (m, 4H). LCMS (ESI) m/e [M+1]⁺=278.

Example BB66: Synthesis of 1-(2-bromo-6-(methylsulfonyl)pyridin-4-yl)-4-methylpiperidin-4-ol

Step 1: 1-(2,6-dibromopyridin-4-yl)-4-methylpiperidin-4-ol

To a solution of 2,6-dibromo-4-nitropyridine (2.0 g, 7.1 mmol) in DMSO (30 mL) was added K₂CO₃ (2.0 g, 14.2 mmol) and 4-methylpiperidin-4-ol (899 mg, 7.8 mmol) at 0° C. under N₂. The mixture was stirred for 2 hr at 25° C. under N₂. The mixture was poured into water (20 mL) and extracted with EtOAc (30 mL, 20 mL). The combined organic phase was washed with brine (50 mL, 30 mL), dried over Na₂SO₄, filtered and concentrated to give the residue which was purified by column chromatography (SiO₂, PE/EA=100/1 to 0/1). Compound of 1-(2,6-dibromopyridin-4-yl)-4-methylpiperidin-4-ol to give the product (1.4 g, 56% yield) was obtained as a gray solid. LCMS (ESI) m/e [M+1]⁺=350.8.

Step 2: 1-(2-bromo-6-(methylthio)pyridin-4-yl)-4-methylpiperidin-4-ol

To a solution of 1-(2,6-dibromopyridin-4-yl)-4-methylpiperidin-4-ol (1.4 g, 4.0 mmol) in DMF (20 mL) was added sodium methanethiolate (336 mg, 4.8 mmol) at 0° C. under N₂. The reaction mixture was stirred for 3 hr at 25° C. under N₂. The mixture was poured into water (10 mL) and extracted with EtOAc (30 mL, 20 mL). The combined organic phase was washed with brine (30 mL, 20 mL), dried over Na₂SO₄, filtered and concentrated to give the residue. The crude product was purified by column chromatography (SiO₂, PE:EA=100/1 to 0/1). Compound of 1-(2-bromo-6-(methylthio)pyridin-4-yl)-4-methylpiperidin-4-ol (1.4 g, 95% yield) was obtained as a light yellow solid. LCMS (ESI) m/e [M+1]⁺=319.

Step 3: 1-(2-bromo-6-(methylsulfonyl)pyridin-4-yl)-4-methylpiperidin-4-ol

To a solution of 1-(2-bromo-6-(methylthio)pyridin-4-yl)-4-methylpiperidin-4-ol (1.1 g, 8.7 mmol) in H₂O/MeOH (1/1, 30 mL) was added oxone (4.3 g, 6.9 mmol) at 25° C. under N₂. The reaction mixture was stirred for 5 hr at 25° C. under N₂. The mixture was filtered to give the filtrate, which was poured into Na₂SO₃ aqueous solution (20 mL) and extracted with EtOAc (30 mL, 20 mL). The combined organic phase was washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated to give the residue. The crude was purified by column chromatography (SiO₂, PE:EA=100/1 to 0/1). Compound of 1-(2-bromo-6-(methylsulfonyl)pyridin-4-yl)-4-methylpiperidin-4-ol (412 mg, 34% yield) was obtained as a white solid. ¹H NMR (DMSO) δ 7.30-7.31 (d, J=2.4, 1H) 7.21-7.22 (d, J=2.0, 1H) 4.48 (s, 1H) 3.5-3.7 (m, 2H) 3.31-3.34 (m, 2H) 3.21 (s, 3H) 1.51-1.52 (m, 4H) 1.14 (s, 3H). LCMS (ESI) m/e [M+1]⁺=349.

Example BB67: Synthesis of 2-chloro-4-((trans)-3-methoxycyclobutyl)-6-(methylsulfonyl)pyridine and 2-chloro-4-(cis)-3-methoxycyclobutyl)-6-(methylsulfonyl)pyridine

Step 1: Synthesis of 3-hydroxycyclobutane-1-carbonitrile

A solution of 3-oxocyclobutane-1-carbonitrile (5 g, 52.57 mmol) in MeOH was treated with NaBH₄ (2.98 g, 78.86 mmol) for 2 h at rt under nitrogen atmosphere. The reaction was quenched with water/ice at 0° C. The resulting mixture was extracted with EtOAc (3×80 mL). The combined organic layers were washed with water (3×50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

Step 2: Synthesis of 3-(benzyloxy)cyclobutane-1-carbonitrile

To a solution of 3-hydroxycyclobutane-1-carbonitrile (3.90 g, 40.15 mmol) in DMF (40 mL) was added NaH (2.01 g, 52.20 mmol, 60% wt) at 0° C. The mixture was stirred for 15 min. BnBr (8.24 g, 48.18 mmol) was added and the mixture was allowed to warm to rt and stirred at rt for 2 h. The resulting mixture was extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (3×40 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (EtOAc/PE=0-20%) to give the product (7.01 g, 93% yield). ¹H NMR (400 MHz, Chloroform-d) δ 7.43-7.34 (m, 2H), 7.34 (m, 3H), 4.45 (s, 2H), 4.01 (m, 1H), 2.74-2.63 (m, 2H), 2.67-2.56 (m, 1H), 2.49-2.38 (m, 1H), 2.38 (m, 1H).

Step 3: Synthesis of 3-(benzyloxy)-1-(2,6-dichloropyridin-4-yl)cyclobutane-1-carbonitrile

To a stirred mixture of 2,4,6-trichloropyridine (3 g, 16.44 mmol) and 3-(benzyloxy)cyclobutane-1-carbonitrile (3.08 g, 16.44 mmol) in THF (60 mL) was added LiHMDS (23.02 mL, 23.02 mmol, 1M in THF) dropwise portions at −10° C. under nitrogen atmosphere. The resulting mixture was stirred for 2 h at rt under nitrogen atmosphere. The reaction was quenched with water/ice at 0° C. and the resulting mixture was extracted with EtOAc (3×80 mL). The combined organic layers were washed with water (3×60 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (EtOAc/PE=0-20%) to give the product (4.5 g, 82% yield). LCMS (ESI) m/e [M+1]⁺=333.

Step 4: Synthesis of 3-(benzyloxy)-1-(2,6-dichloropyridin-4-yl)cyclobutane-1-carboxylic acid

A solution of 3-(benzyloxy)-1-(2,6-dichloropyridin-4-yl)cyclobutane-1-carbonitrile (4.50 g, 13.50 mmol) in H₂O (50 mL) was treated with KOH (2.27 g, 40.51 mmol) for 2 h at 105° C. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI) m/e [M+1]⁺=352.

Step 5: Synthesis of 4-[3-(benzyloxy)cyclobutyl]-2,6-dichloropyridine

A solution of 3-(benzyloxy)-1-(2,6-dichloropyridin-4-yl)cyclobutane-1-carboxylic acid (4.50 g, 12.77 mmol) in pyridine (40 mL) was treated with Py-HCl (1.47 g, 12.77 mmol) for 2 h at 90° C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (EtOAc/PE=0-40%) to give the product (2.2 g, 55% yield). LCMS (ESI) m/e [M+1]⁺=308.

Step 6: Synthesis of 3-(2,6-dichloropyridin-4-yl)cyclobutan-1-ol

A solution of 4-[3-(benzyloxy)cyclobutyl]-2,6-dichloropyridine (2.20 g, 7.13 mmol) in HCl (12 N) (20 mL) was stirred 2 h at 50° C. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (3×30 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (PE/EtOAc=50%) to give the product (880 mg, 56% yield). LCMS (ESI) m/e [M+1]⁺=218.

Step 7: Synthesis of 2,6-dichloro-4-(3-methoxycyclobutyl)pyridine

To a solution of 3-(2,6-dichloropyridin-4-yl)cyclobutan-1-ol (830 mg, 3.80 mmol) in DMF was added NaH (182 mg, 4.56 mmol, 60% wt) at 0° C. The mixture was stirred for 15 min at this temperature and then CH₃I (810 mg, 5.70 mmol) was added and the mixture was allowed to warm to rt and stirred for 2 h. The reaction was quenched with water/ice at 0° C. The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (3×20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc=5:1) to give the product (520 mg, 58% yield). LCMS (ESI) m/e [M+1]⁺=232.

Step 8: Synthesis of 2-chloro-4-(3-methoxycyclobutyl)-6-(methylsulfanyl)pyridine

A mixture of 2,6-dichloro-4-(3-methoxycyclobutyl)pyridine (520 mg, 2.24 mmol) and (methylsulfanyl)sodium (235 mg, 3.36 mmol) in DMF (6 mL) was stirred for 2 h at rt. The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (3×20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI) m/e [M+1]⁺=244.

Step 9: Synthesis of 2-chloro-6-methanesulfonyl-4-(3-methoxycyclobutyl)pyridine; 2-chloro-4-((trans)-3-methoxycyclobutyl)-6-(methylsulfonyl)pyridine; 2-chloro-4-((cis)-3-methoxycyclobutyl)-6-(methylsulfonyl)pyridine

A solution of 2-chloro-4-(3-methoxycyclobutyl)-6-(methylsulfanyl)pyridine (520 mg, 2.13 mmol) in THF (10 mL) was treated with NaIO₄ (912.61 mg, 4.26 mmol) for 2 h at 0° C. under nitrogen atmosphere followed by the addition of RuCl₃·H₂O (24.05 mg, 0.10 mmol) in H₂O (5 mL) dropwise portions at 0° C. The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (3×30 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc=3:1) to give the product (268 mg, 45% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.92-7.81 (s, 1H), 7.77 (s, 1H), 3.88 (tt, J=7.7, 6.6 Hz, 1H), 3.30 (s, 3H), 3.34-3.20 (m, 1H), 3.17 (s, 3H), 2.70 (m, 2H), 1.98 (m, 2H). LCMS (ESI) m/e [M+1]⁺=276.

The racemic compound was separated by ACHIRAL-SFC (Column: DAICEL DCpak P4VP, 3×25 cm, 5 μm; Mobile Phase A: CO₂, Mobile Phase B: IPA (0.5% 2M NH₃-MeOH); Flow rate: 60 mL/min; Gradient: isocratic 15% B; Column Temperature: 35° C.; Back Pressure: 100 bar; Wave Length: 254 nm) to give the trans product (179 mg, RT₁: 4.78 min). ¹H NMR (300 MHz, DMSO-d₆) δ 7.94-7.88 (m, 1H), 7.84 (s, 1H), 4.12-3.98 (m, 1H), 3.76 (p, J=7.9 Hz, 1H), 3.31 (s, 3H), 3.19 (s, 3H), 2.51-2.33 (m, 4H). LCMS (ESI) m/e [M+1]⁺=276.

Cis product (1.31 g, RT₂: 5.28 min): ¹H NMR (300 MHz, DMSO-d₆) δ 7.91-7.86 (m, 1H), 7.86-7.74 (m, 1H), 3.97-3.81 (m, 1H), 3.31 (s, 3H), 3.32-3.20 (m, 1H), 3.18 (s, 3H), 2.71 (m, 2H), 2.08-1.90 (m, 2H). LCMS (ESI) m/e [M+1]⁺=276.

Example A1: Synthesis of N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(pyridazin-3-yl)pyridin-2-yl)acetamide

Step 1: 4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

A mixture of 5-bromo-4-chloropyridin-2-amine (1.0 g, 4.8 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.3 g, 5.3 mmol), KOAc (1.4 g, 14.5 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (197 mg, 0.2 mmol) in 1,4-dioxane (20 mL) was stirred at 115° C. under N₂ for 6 h. After cooled to room temperature, the mixture was diluted with H₂O (30 mL) and the resulting solution was extracted with EA (30 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE/EA=1:1 to 0:1) to give 4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.5 g, crude). MS (ESI) m/e [M+1]⁺ 173.

Step 2: 4-chloro-5-(pyridazin-3-yl)pyridin-2-amine

A mixture of 4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (478 mg, 1.9 mmol), 3-bromopyridazine (100 mg, 0.6 mmol), Na₂CO₃ (133 mg, 1.3 mmol) and Pd(dppf)Cl₂ (44 mg, 0.06 mmol) in CH₃CN (10 mL) and H₂O (2 mL) was stirred at 120° C. for 10 mins in microwave reactor. After cooled to room temperature, the mixture was diluted with H₂O (20 mL) and the resulting solution was extracted with EA (30 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE/EA=1:1 to 0:1) to give 4-chloro-5-(pyridazin-3-yl)pyridin-2-amine (51 mg, 39.4%). MS (ESI) m/e [M+1]⁺ 207.

Step 3: N-(4-chloro-5-(pyridazin-3-yl)pyridin-2-yl)acetamide

To a solution of N-(4-chloro-5-(pyridazin-3-yl)pyridin-2-yl)acetamide (40 mg, 0.2 mmol) in pyridine (2 mL) was added acetyl chloride (17 mg, 0.2 mmol) dropwise at 0° C. Then the mixture was stirred at RT for 2 h. Upon completion of the reaction, the mixture was concentrate and the residue was diluted with water (5 mL), then the mixture was extracted with EA (10 mL×3) and citric acid (10 mL), dried over anhydrous Na₂SO₄, concentrated under vacuum to give N-(4-chloro-5-(pyridazin-3-yl)pyridin-2-yl)acetamide (45 mg, 93%). (ESI) m/e [M+1]⁺ 249.

Step 4: N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(pyridazin-3-yl)pyridin-2-yl)acetamide

A mixture of N-(4-chloro-5-(pyridazin-3-yl)pyridin-2-yl)acetamide (20.0 mg, 0.08 mmol), 3-(methylsulfonyl)aniline (27.0 mg, 0.16 mmol), Cs₂CO₃ (78 mg, 0.24 mmol), Xantphos (5 mg, 8 μmol) and Pd₂(dba)₃ (7 mg, 8 μmol) in 1,4-dioxane (2 mL) was stirred at 110° C. for 12 h under nitrogen atmosphere. After cooled to room temperature, the mixture was diluted with H₂O (20 mL) and the resulting solution was extracted with EA (30 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crude product was purified by Prep-HPLC (column: Phenomenex Gemini-NX 150×30 mm×5 um; phase: A-H₂O (10 mM NH₄HCO₃); B-ACN; B %: 15%-35% in 20 min) to give N-(4-((3-(methylsulfonyl) phenyl)amino)-5-(pyridazin-3-yl)pyridin-2-yl)acetamide (1.8 mg, 6%). ¹H NMR (400 MHz, MeOD-d₄) δ 9.32 (d, J=4.4 Hz, 1H), 8.59 (s, 1H), 8.36 (d, J=8.8 Hz, 1H), 8.05 (s, 1H), 8.03-7.96 (m, 2H), 7.86-7.78 (m, 2H), 6.70 (s, 1H), 3.20 (s, 3H), 2.24 (s, 3H). MS (ESI) m/e [M+1]⁺ 384.

Example A2: Synthesis of N-[4-[(3-methanesulfonylphenyl)amino]-5-(oxolan-2-yl)pyridin-2-yl]acetamide

Step 1: 5-Bromo-2-chloro-N-(3-methanesulfonylphenyl)pyridin-4-amine

A mixture of 5-bromo-2-chloro-4-iodopyridine (3.00 g, 9.42 mmol), Cs₂CO₃ (6.14 g, 18.848 mmol), Xantphos (1.09 g, 1.88 mmol), 3-methanesulfonylaniline (1.77 g, 10.37 mmol), Pd₂(dba)₃ (0.86 g, 0.942 mmol) in 1,4-dioxane (30 mL) was stirred for overnight at 100° C. under nitrogen atmosphere. After cooled to room temperature, the mixture was diluted with H₂O (20 mL) and the resulting solution was extracted with EA (80 mL×3). The resulting mixture was washed with brine (10 mL), dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum and the residue was purified by combi-flash (EA/PE=0-15%) to give 5-Bromo-2-chloro-N-(3-methanesulfonylphenyl)pyridin-4-amine (1.6 g, 46.95% yield). LCMS (ESI) m/e [M+1]⁺ 362.

Step 2: 5-bromo-N²-(4-methoxybenzyl)-N⁴-(3-(methylsulfonyl)phenyl)pyridine-2,4-diamine

Into a 20-mL sealed tube, were placed 5-bromo-2-chloro-N-(3-methanesulfonylphenyl)pyridin-4-amine (1.5 g, 4.148 mmol) and PMBNH₂ (5 mL). The resulting solution was stirred overnight at 135° C. After cooled to room temperature, the residue was purified by prep-HPLC (column: Phenomenex Gemini-NX; phase: A-H₂O (0.05% TFA); B-Acetonitrile, B %: 40%-60% in 20 min) to give 5-bromo-N2-(4-methoxybenzyl)-N4-(3-(methylsulfonyl)phenyl)pyridine-2,4-diamine (600 mg, 31%). LCMS (ESI) m/e [M+1]⁺ 462.

Step 3: 5-(furan-2-yl)-N⁴-(3-methanesulfonylphenyl)-N²-[(4-methoxyphenyl)methyl]pyridine-2,4-diamine

A mixture of 5-bromo-N4-(3-methanesulfonylphenyl)-N2-[(4-methoxyphenyl)methyl]pyridine-2,4-diamine (420 mg, 0.91 mmol), K₂CO₃ (251 mg, 1.82 mmol), furan-2-ylboronic acid (152 mg, 1.36 mmol) and Pd(PPh₃)₄ (105 mg, 0.091 mmol) in 1,4-dioxane (4.00 mL) and H₂O (0.80 mL) was stirred for 2 h at 100° C. under nitrogen atmosphere. After cooled to room temperature, the mixture was diluted with H₂O (20 mL) and the resulting solution was extracted with EA (80 mL×3). The combined organic layer was washed with 100 mL of brine, dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum and the residue was purified by Prep-TLC (MeOH/DCM=1:15) to give 5-(furan-2-yl)-N⁴-(3-methanesulfonylphenyl)-N²-[(4-methoxyphenyl)methyl]pyri dine-2,4-diamine (270 mg, 66%). LCMS (ESI) m/e [M+1]⁺ 450.

Step 4: N²-(4-methoxybenzyl)-N4-(3-(methylsulfonyl)phenyl)-5-(tetrahydrofuran-2-yl)pyridine-2,4-diamine

Into a 20-mL pressure tank reactor were placed 5-(furan-2-yl)-N4-(3-methanesulfonylphenyl)-N2-[(4-methoxyphenyl)methyl]pyridine-2,4-diamine (270 mg, 0.60 mmol), i-PrOH (5 mL), hydrochloric acid (12 M, 0.05 mL) and Pd(OH)₂/C (10%, 168 mg), the resulting solution was stirred overnight at 65° C. under hydrogen atmosphere (10 atm). After cooled to room temperature, the mixture was diluted with H₂O (20 mL) and the resulting solution was extracted with EA (50 mL×3). The reaction mixture was cooled to rt with a water bath. The resulting solution was extracted with EA (50 mL×3) and the organic layers combined. The combined organic layers were washed with 100 mL of brine, dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum and the residue was purified by Prep-TLC (MeOH/DCM=1:12) to give N²-(4-methoxybenzyl)-N⁴-(3-(methylsulfonyl)phenyl)-5-(tetrahydrofuran-2-yl) pyridine-2,4-diamine (80 mg, 29%). LCMS (ESI) m/e [M+1]⁺ 454.

Step 5: N⁴-(3-(methylsulfonyl)phenyl)-5-(tetrahydrofuran-2-yl)pyridine-2,4-diamine

A mixture of N⁴-(3-methanesulfonylphenyl)-N²-[(4-methoxyphenyl)methyl]-5-(oxolan-2-yl)pyridine-2,4-diamine (80 mg) and TFA (2 mL) was stirred for 1 h at 70° C. After cooled to room temperature, the solvent was removed in vacuo and the residue was purified by prep-HPLC (column: Phenomenex Gemini-NX; phase: A-H₂O (0.05% TFA); B-Acetonitrile, B %: 13%-20% in 20 min) to give N⁴-(3-(methylsulfonyl)phenyl)-5-(tetrahydrofuran-2-yl)pyridine-2,4-diamine (50 mg, 85%). LCMS (ESI) m/e [M+1]⁺ 334.

Step 6: N-[4-[(3-methanesulfonylphenyl)amino]-5-(oxolan-2-yl)pyridin-2-yl]acetamide

A mixture of N4-(3-methanesulfonylphenyl)-5-(oxolan-2-yl)-1,6-dihydropyridine-2,4-diamine (50 mg, 0.15 mmol), pyridine (1 mL) and acetic anhydride (12 mg, 0.12 mmol) was stirred for 1 h at 80° C. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with 20 mL of water. The resulting solution was extracted with EA (30 mL×3) and the combined organic layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by prep-HPLC (column: Phenomenex Gemini-NX; phase: A-H₂O (0.1% FA); B-Acetonitrile, B %: 35%-55% in 8 min) to give N-[4-[(3-methanesulfonylphenyl)amino]-5-(oxolan-2-yl)pyridin-2-yl]acetamide (1.8 mg, 3%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.34 (s, 1H), 8.20 (d, J=6.7 Hz, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 7.73 (s, 1H), 7.60 (d, J=8.9 Hz, 1H), 7.58-7.50 (m, 2H), 5.08-5.03 (m, 1H), 4.10-4.05 (m, 1H), 3.82-3.78 (m, 1H), 3.35 (s, 3H), 2.38-2.34 (m, 1H), 2.03 (s, 3H), 2.00-1.95 (m, 2H), 1.78-1.72 (m, 1H). MS (ES, m/z): [M+H]⁺ 376.

Example A3: Synthesis of N-(5-(1H-imidazol-4-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

Step 1: 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 5-iodo-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-imidazole and 5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

To a solution of 5-iodo-1H-imidazole (2 g, 10.3 mmol) in THF (15 mL) was added NaH (60% in mineral oil, 454 mg, 11.3 mmol) in portions at 0° C. The resulting mixture was stirred for 30 mins at 0° C. Then added a solution of (2-(chloromethoxy)ethyl)trimethylsilane (1.72 g, 10.8 mmol) in THF (5 mL) dropwise with stirring at 0° C. The reaction was warmed to room temperature with stirring for 1 h. The reaction was quenched by saturated NH₄Cl at 0° C. and extracted with EA. The organic layer was washed with brine, dried over Na₂SO₄, concentrated to give the residue and purification by silica gel column with EA/DCM (1:1) to afford a mixture of 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (2.66 g, 79.6%). MS (ESI) m/e [M+1]⁺ 325.

Step 2: 2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridin-4-amine and 2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-4-amine

A mixture of 2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridin-4-amine and 2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-4-amine (966 mg, 4.98 mmol), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (1.39 g, 5.48 mmol), Pd(dppf)Cl₂ (182 mg, 0.25 mmol) and K₂CO₃ (1.37 g, 9.96 mmol) in 1,4-dioxane (18 mL) and H₂O (3 mL) was charged with nitrogen and heated to 90° C. stirred for 1 h. The reaction was cooled to room temperature and diluted with EA, washed with brine, dried and concentrated. The residue was applied onto a silica gel column with EA/PE (1:2) to afford the product (862 mg, 89.2%). MS (ESI) m/e [M+1]⁺ 325.

Step 3: N-(2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridin-4-yl)-6-(methylsulfonyl)pyridin-2-amine and N-(2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-4-yl)-6-(methylsulfonyl)pyridin-2-amine

A mixture of 2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridin-4-amine and 2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-4-amine (412 mg, 1.27 mmol), 2-bromo-6-(methylsulfonyl)pyridine (358 mg, 1.5 mmol), Pd₂dba₃ (58 mg, 0.06 mmol), BINAP (118 mg, 0.19 mmol) and Cs₂CO₃ (829 mg, 2.5 mmol) in 1,4-dioxane (10 mL) was heated to 130° C. and stirred at this temperature for 3 h under nitrogen atmosphere. The reaction was cooled to room temperature, filtered and the filtration was concentrated under vacuum. The residue was applied onto Prep-TLC with DCM/MeOH (30:1) to afford the product (139 mg, 22.9%). MS (ESI) m/e [M+1]⁺ 480.

Step 4: N-(4-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridin-2-yl)acetamide and N-(4-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-2-yl)acetamide

A mixture of N-(2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridin-4-yl)-6-(methylsulfonyl)pyridin-2-amine and N-(2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-4-yl)-6-(methylsulfonyl)pyridin-2-amine (139 mg, 0.29 mmol), acetamide (51 mg, 0.87 mmol), Pd₂dba₃ (26.6 mg, 0.03 mmol), Xantphos (50 mg, 0.09 mmol) and Cs₂CO₃ (189 mg, 0.58 mmol) in 1,4-dioxane (4 mL) was heated at 130° C. for 3 h under nitrogen atmosphere. The reaction was cooled to room temperature, filtered and the filtration was concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (25:1) to afford the product (94 mg, 64.5%). MS (ESI) m/e [M+1]⁺ 502.

Step 5: N-(5-(1H-imidazol-4-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

A solution of N-(4-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridin-2-yl)acetamide and N-(4-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-2-yl)acetamide (94 mg, 0.19 mmol) in TFA (5 mL) was heated to 50° C. stirred for 1 h. Then TFA was removed under vacuum and the residue was treated with NH₃ in MeOH (4 mL, 7M). The solvent was removed under vacuum and the residue was applied onto a C¹⁸ column with CH₃CN/water to afford N-(5-(1H-imidazol-4-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide (31.04 mg, 43.9%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.71 (s, 1H), 12.67 (s, 1H), 10.38 (s, 1H), 9.21 (s, 1H), 8.63 (s, 1H), 8.04-7.93 (m, 2H), 7.88 (s, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.23 (d, J=8.2 Hz, 1H), 3.49 (s, 3H), 2.10 (s, 3H). MS (ESI) m/e [M+1]⁺ 373.

Example A25: synthesis of N-(4-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide

A mixture of N-(4-amino-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide (50 mg, 0.19 mmol), 2-bromo-4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridine (71 mg, 0.23 mmol), Pd₂(dba)₃ (17 mg, 0.019 mmol), BINAP (12 mg, 0.019 mmol) and Cs₂CO₃ (186 mg, 0.57 mmol) in dioxane (5 mL) was stirred for 16 h at 120° C. under nitrogen atmosphere. After cooled to room temperature, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (MeOH/DCM=0-10%) to give the product (0.84 mg, 22%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.39 (s, 1H), 10.58 (s, 1H), 8.96 (s, 1H), 8.65 (s, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.10 (s, 1H), 6.82 (s, 1H), 4.11 (s, 3H), 4.06-4.02 (m, 2H), 3.37 (s, 3H), 2.12 (s, 3H), 1.26-1.24 (m, 1H), 0.61-0.60 (m, 2H), 0.38-0.37 (m, 2H). MS (ESI) m/e [M+1]⁺ 485.

Example A26: synthesis of N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide

A mixture of N-(4-amino-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide (50 mg, 0.19 mmol), 2-bromo-4-isopropoxy-6-(methylsulfonyl)pyridine (67 mg, 0.23 mmol), Pd₂(dba)₃ (17 mg, 0.019 mmol), BINAP (12 mg, 0.019 mmol) and Cs₂CO₃ (186 mg, 0.57 mmol) in dioxane (5 mL) was stirred for 16 h at 120° C. under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (MeOH/DCM=0-10%) to give the product (4.20 mg, 4%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.25 (s, 1H), 10.52 (s, 1H), 8.91 (s, 1H), 8.59 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.02 (s, 1H), 6.74 (s, 1H), 4.95-4.66 (m, 1H), 4.07 (s, 3H), 3.32 (s, 3H), 2.07 (s, 3H), 1.28 (d, J=4.0 Hz, 6H). MS (ESI) m/e [M+1]⁺ 473.

The following Examples were prepared in a similar manner to the product Example A3:

¹H NMR and LC/MS Example Compound Chemical Name m/z (M + 1) A4

N-(5-(5-methylpyrazin- 2-yl)-4-((3- (methylsulfonyl)phenyl) amino)pyridin- 2-yl)acetamide ¹H NMR (400 MHz, CD₃OD) δ: 9.00 (s, 1 H), 8.60 (s, 1 H), 8.58 (s, 1 H), 8.16 (s, 1 H), 7.88 (s, 1 H), 7.69-7.56 (m, 3 H), 3.20 (s, 3 H), 2.58 (s, 3 H), 2.12 (s, 3 H). MS (ESI) m/e [M + 1]⁺ 398. A5

N-(4-((3- (methylsulfonyl) phenyl)amino)-5- (pyrazin-2-yl)pyridin- 2-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.55 (s, 1H), 10.43 (s, 1H), 9.25 (s, 1H), 8.74-8.68 (m, 2H), 8.61 (s, 1H), 8.17 (s, 1H), 7.80 (s, 1H), 7.66- 7.58 (m, 3H), 3.27 (s, 3H), 2.07 (s, 3H). MS (ESI) m/e [M + 1]⁺ 384. A6

N-(5-(2,6- dimethylpyrimidin- 4-yl)-4-((3- (methylsulfonyl)phenyl) amino)pyridin- 2-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.73 (s, 1H), 10.60 (s, 1H), 8.82 (s, 1H), 8.19 (s, 1H), 7.90- 7.85 (m, 2H), 7.74- 7.58 (m, 3H), 3.33 (s, 3H), 3.30 (s, 3H), 2.68 (s, 3H), 2.07 (s, 3H). MS (ESI) m/e [M + 1]⁺ 412. A7

N-(4-((3- (methylsulfonyl)phenyl) amino)-5-(2- oxopyrrolidin-1- yl)pyridin-2- yl)acetamide ¹H NMR (300 MHz, DMSO-d₆) δ 10.40 (s, 1H), 8.45 (s, 1H), 8.05- 8.00 (m, 2H), 7.75-7.70 (m, 1H), 7.68-7.47 (m, 3H), 3.65-3.60 (m, 2H), 2.45 (s, 3H), 2.10-2.05 (m, 2H), 2.06 (s, 3H). 2.05-2.00 (m, 2H), MS (ESI) m/e [M + 1]⁺ 389. A8

N-(5-(1-methyl-1H- pyrazol-4-yl)-4- ((6-(methylsulfonyl) pyridin-2- yl)amino)pyridin- 2-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 8.91 (s, 1H), 8.71 (s, 1H), 8.21 (s, 1H), 8.02 (s, 1H), 7.95-7.85 (m, 1H), 7.69 (s, 1H), 7.50-7.40 (m, 1H), 7.35-7.25 (m, 1H), 3.86 (s, 3H), 3.28 (s, 3H), 2.06 (s, 3H). MS (ESI) m/e [M + 1]⁺ 387. A9

N-(5-(furan-2-yl)- 4-((4-methyl-6- (methylsulfonyl) pyridin-2- yl)amino)pyridin- 2-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.52 (s, 1H), 9.06 (s, 1H), 8.74 (s, 1H), 8.44 (s, 1H), 7.77 (d, J = 0.7 Hz, 1H), 7.38- 7.33 (m, 1H), 7.17-7.11 (m, 1H), 6.78 (d, J = 3.4 Hz, 1H), 6.61 (d, J = 3.4 Hz, 1H), 3.24 (s, 3H), 2.35 (s, 3H), 2.07 (s, 3H). MS (ESI) m/e [M + 1]⁺ 387. A10

N-(5-(1-methyl-1H- 1,2,4-triazol-3-yl)- 4-((3- (methylsulfonyl)phenyl) amino)pyridin- 2-yl)acetamide ¹H NMR (400 MHz, CDCl₃) δ = 10.16 (s, 1H), 8.98 (s, 1H), 8.25 (s, 1H), 8.12 (s, 2H), 7.97 (s, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.66-7.58 (m, 2H), 4.03 (s, 3H), 3.21 (s, 3H), 2.17 (s, 3H). MS (ESI) m/e [M + 1]⁺ 387. A11

N-(4-((3-methoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)- 5-(1-methyl-1H-pyrazol- 4-yl)pyridin- 2-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 9.25 (s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 8.12 (s, 1H), 7.77 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.43 (s, 3H), 2.11 (s, 3H). MS (ESI) m/e [M + 1]⁺ 417. A12

N-(4-((4-isopropoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)- 5-(1H-pyrazol-1- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.59 (s, 1H), 9.65 (s, 1H), 9.02 (s, 1H), 8.34 (s, 1H), 8.30 (d, J = 2.4 Hz, 1H), 7.90 (s, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.85 (s, 1H), 6.70- 6.60 (m, 1H), 4.81 (s, 1H), 3.37 (s, 3H), 2.11 (s, 3H), 1.31 (d, J = 6.0 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 431. A13

N-(4-((4-methyl-6- (methylsulfonyl)pyridin- 2-yl)amino)- 5-(1-(2-morpholino- 2-oxoethyl)-1H- pyrazol-3-yl)pyridin- 2-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.44 (s, 1H), 10.50 (s, 1H), 9.26 (s, 1H), 8.63 (s, 1H), 7.89 (d, J = 4.0 Hz, 1H), 7.46 (s, 1H), 7.16 (s, 1H), 6.93 (d, J = 4.0 Hz, 1H), 5.38 (s, 2H), 3.68-3.64 (m, 2H), 3.60-3.55 (m, 4H), 3.54-3.50 (m, 2H), 3.48 (s, 3H), 2.42 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M + 1]⁺ 514. A14

N-(5-(1-(2-hydroxyethyl)- 1H-pyrazol- 3-yl)-4-((4-isopropoxy-6- (methylsulfonyl) pyridin-2- yl)amino)pyridin- 2-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.43 (s, 1H), 10.42 (s, 1H), 9.19 (s, 1H), 8.62 (s, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.06 (s, 1H), 6.91 (d, J = 2.3 Hz, 1H), 6.74 (s, 1H), 5.00 (s, 1H), 4.90-4.83 (m, 1H), 4.36-4.29 (m, 2H), 3.90-3.83 (m, 2H), 3.46 (s, 3H), 2.11 (s, 3H), 1.34 (d, J = 6.0 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 475. A15

N-(5-(1-(2-methoxyethyl)- 1H-pyrazol- 3-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin- 2-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.57 (s, 1H), 10.54 (s, 1H), 9.21 (s, 1H), 8.65 (s, 1H), 7.92 (d, J = 4.1 Hz, 1H), 7.47 (s, 1H), 7.17 (s, 1H), 6.95 (d, J = 4.1 Hz, 1H), 4.49- 4.45 (m, 2H), 3.80-3.75 (m, 2H), 3.47 (s, 3H), 3.28 (s, 3H), 2.45 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M + 1]⁺ 445. A16

N-(6-cyano-4′- ((4-isopropoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)- [2,3′-bipyridin]- 6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (s, 1H), 10.61 (s, IH), 9.04 (s, 1H), 8.68 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.20- 8.15 (m, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.16-7.04 (m, 1H), 6.75-6.70 (m, 1H), 4.80-4.46 (m, 1H), 3.39 (s, 3H), 2.13 (s, 3H), 1.34 (d, J = 5.9 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 467. A17

N-(5-cyano-4′- ((4-isopropoxy-6- (methylsulfonyl) pyridin-2-yl)amino)- [2,3′-bipyridin]- 6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.92 (s, 1H), 10.57 (s, 1H), 9.18 (s, 1H), 9.10 (s, 1H), 8.77 (s, 1H), 8.39 (d, J = 8.6 Hz, 1H), 8.22 (d, J = 8.6 Hz, 1H), 7.04 (s, 1H), 6.84 (s, 1H), 4.89-4.83 (m, 1H), 3.37 (s, 3H), 2.08 (s, 3H), 1.29 (d, J = 5.9 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 467. A18

N-(5-(1H-imidazol- 1-yl)-4-((4- isopropoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)pyridin- 2-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.59 (s, 1H), 8.91 (s, 1H), 8.83 (s, 1H), 8.13 (s, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.42 (s, 1H), 7.14 (s, 1H), 7.00 (d, J = 1.9 Hz, 1H), 6.86 (s, 1H), 4.73-4.67 (m, 1H), 3.33 (s, 3H), 2.10 (s, 3H), 1.30 (d, J = 6.0 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 431. A19

N-(5-(1-cyclobutyl- 1H-pyrazol-3-yl)- 4-((4-isopropoxy-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin- 2-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.49 (s, 1H), 10.50 (s, 1H), 9.12 (s, 1H), 8.66 (s, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.07 (s, 1H), 6.95 (d, J = 2.2 Hz, 1H), 6.72 (s, 1H), 5.07-4.96 (m, 1H), 4.95- 4.79 (m, 1H), 3.45 (s, 5H), 2.71-2.53 (m, 2H), 2.50-2.42 (m, 3H), 2.12 (s, 3H), 1.91-1.81 (m, 2H), 1.35 (d, J = 5.9 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 485. A20

N-(5-(2-aminopropan- 2-yl)-4′-((4- methyl-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′- bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.88 (s, 1H), 10.54 (s, 1H), 9.23 (s, 1H), 8.99-8.95 (m, 1H), 8.85 (s, 1H), 8.45- 8.40 (m, 2H), 8.26-8.18 (m, 2H), 7.46 (s, 1H), 7.24 (s, 1H), 3.45 (s, 3H), 2.44 (s, 3H), 2.13 (s, 3H), 1.73 (s, 6H). MS (ESI) m/e [M + 1]⁺ 455. A21

N-(5-(1H-imidazol- 4-yl)-4-((4-(2- methoxyethoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin- 2-yl)acetamide MS (ESI) m/e [M + 1]⁺ 447. A22

N-(5-(1H-imidazol-4- yl)-4-((4-methyl- 6-(methylsulfonyl)pyridin-2- yl)amino)pyridin- 2-yl)acetamide MS (ESI) m/e [M + 1]⁺ 387. A23

N-(5-(1H-imidazol- 4-yl)-4-((4- isopropoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)pyridin- 2-yl)acetamide MS (ESI) m/e [M + 1]⁺ 431. A24

N-(4-((6-(methylsulfonyl) pyridin-2- yl)amino)-5-(pyridazin- 3-yl)pyridin-2- yl)acetamide Molecular Weight: 384 A27

N-(4-((4-((2S,6R)-2,6- dimethylmorpholino)-6- (methylsulfonyl)pyridin- 2-yl)amino)- 5-(6-methoxypyridazin- 3-yl)pyridin-2- yl)acetamide Molecular Weight: 528 A28

N-(5-(6-methoxypyridazin- 3-yl)-4-((6- (methylsulfonyl)- [1,3]dioxolo[4,5- c]pyridin-4-yl) amino)pyridin-2- yl)acetamide Molecular Weight: 459 A29

N-(5-(6-isopropoxypyridazin- 3-yl)-4- ((4-methyl-6- (methylsulfonyl)pyridin- 2-yl)amino)pyridin- 2-yl)acetamide Molecular Weight:457 A30

N-(5-(6-isopropoxypyridazin- 3-yl)-4- ((4-methoxy-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin- 2-yl)acetamide Molecular Weight: 473 A31

N-(5-(6-isopropoxypyridazin- 3-yl)-4- (4-(methoxy-d3)-6- (methylsulfonyl)pyridin-2- ylamino)pyridin- 2-yl)acetamide Molecular Weight: 476

Example B1: Synthesis of N-(4′-((3-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

Step 1: tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate

To a mixture of 5-bromo-2-chloropyridin-4-amine (30 g, 144.6 mmol), DMAP (1.8 g, 14.4 mmol), TEA (43.9 g, 434.0 mmol) in DCM (300 mL) was added Boc₂O (38.0 g, 173.0 mmol) dropwise at room temperature and the resulting mixture was stirred at this temperature for 12 h. Upon completion of the reaction, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE/EA=20:1 to 5:1) to give tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (40.0 g, 90.2% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.35 (s, 1H), 8.25 (s, 1H), 7.19 (s, 1H), 1.56 (s, 9H). MS (ESI) m/e [M+1]⁺ 307.

Step 2: tert-butyl (6′-chloro-[2,3′-bipyridin]-4′-yl)carbamate

A mixture of tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (5.0 g, 16.3 mmol), 2-bromopyridine (2.8 g, 17.9 mmol), Pd(PPh₃)₂Cl₂ (1.1 g, 1.6 mmol), Pd(PPh₃)₄ (1.9 g, 1.6 mmol) and Sn₂Me₆ (8.0 g, 24.0 mmol) in dioxane (50 mL) was stirred at 110° C. for 12 h under nitrogen atmosphere. After cooled to room temperature, the mixture was diluted with KF—H₂O (50 mL) and extracted with EA (50 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE/EA=20:1 to 10:1) to give tert-butyl (6′-chloro-[2,3′-bipyridin]-4′-yl)carbamate (880 mg, 18.0%). MS (ESI) m/e [M+1]⁺ 306.

Step 3: tert-butyl (6′-acetamido-[2,3′-bipyridin]-4′-yl)carbamate

A mixture of tert-butyl (6′-chloro-[2,3′-bipyridin]-4′-yl)carbamate (2.0 g, 6.5 mmol), acetamide (773 mg, 13.1 mmol), Cs₂CO₃ (6.3 g, 19.5 mmol), Xant-Phos (753 mg, 1.3 mmol) and Pd₂(dba)₃ (595 mg, 0.65 mmol) in dioxane (20 mL) was stirred at 110° C. for 12 h under nitrogen atmosphere. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with water (20 mL). The resulting solution was extracted with EA (30 mL×3) and the combined organic layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE/EA=3:1 to 1:1) to give tert-butyl (6′-acetamido-[2,3′-bipyridin]-4′-yl)carbamate (1.3 g, 61.0%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 10.50 (s, 1H), 8.98 (s, 1H), 8.73 (s, 1H), 8.68-8.63 (m, 1H), 8.10-8.05 (m, 1H), 7.98 (m, 1H), 7.45-7.40 (m, 1H), 2.11 (s, 3H), 1.50-1.47 (m, 9H). MS (ESI) m/e [M+1]⁺ 329.

Step 4: N-(4′-amino-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of tert-butyl (6′-acetamido-[2,3′-bipyridin]-4′-yl)carbamate (4.0 g, 12.2 mmol) in TFA (20 mL) and DCM (20 mL) was stirred at room temperature for 3 h. Upon completion of the reaction, the solvent was removed in vacuo and the residue diluted with water. NaHCO₃ (40 mL) was added to adjust the pH value to 9 and the resulting solution was extracted with EA (40 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated in vacuo to give N-(4′-amino-[2,3′-bipyridin]-6′-yl)acetamide (2.7 g, 97.1%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.35 (s, 1H), 8.60 (d, J=4.9 Hz, 1H), 8.42 (s, 1H), 7.90-7.86 (m, 2H), 7.38 (s, 1H), 6.88 (s, 2H), 7.33-7.28 (m, 1H), 2.09 (s, 3H). MS (ESI) m/e [M+1]⁺ 229.

Step 5: N-(4′-((3-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of N-(4′-amino-[2,3′-bipyridin]-6′-yl)acetamide (120 mg, 0.53 mmol), 1-bromo-3-(methyl sulfonyl)benzene (120 mg, 0.5 mmol), Pd₂dba₃ (80 mg, 0.09 mmol), Xant-Phos (60 mg, 0.1 mmol) and Cs₂CO₃ (300 mg, 0.92 mmol) in dioxane (6 mL) was stirred at 130° C. under N₂ in a sealed tube for 3 h. The reaction mixture was filtered and the solid was washed with EA (10 mL). The filtrate was concentrated and the residue was purified by prep-TLC (DCM/MeOH=20:1) to give N-(4′-((3-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide (24 mg, 12%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.52 (s, 1H), 10.50 (s, 1H), 8.74-8.66 (m, 2H), 8.18 (s, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.99-7.90 (m, 1H), 7.83 (s, 1H), 7.67-7.57 (m, 3H), 7.45-7.37 (m, 1H), 3.29 (s, 3H), 2.07 (s, 3H). MS (ESI) m/e [M+1]⁺ 383.

The following Examples were prepared in a similar manner to the product Example B1:

¹H NMR and LC /MS Example Compound Chemical Name m/z (M + 1) B2

N-(4-((6- (methylsulfonyl)pyridin-2- yl)amino)-[3,3′-bipyridin]-6- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 10.54 (s, 1H), 9.09 (s, 1H), 8.77 (s, 1H), 8.64 (s, 1H), 8.57 - 8.55 (m, 1H), 8.19 - 8.17 (m, 1H), 7.88 - 7.84 (m, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8 Hz, 1H), 3.28 (s, 3H), 2.08 (s, 3H). MS (ESI) m/e [M + 1]⁺ 384. B3

N-(4′-(phenylamino)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.41 (s, 1H), 10.36 (s, 1H), 8.75 - 8.65 (m, 1H), 8.65 (s, 1H), 8.10 - 8.05 (m, 2H), 8.00 - 7.90 (m, 1H), 7.42 - 7.34 (m, 2H), 7.31 (s, 2H), 7.29 (s, 1H), 7.15 - 7.10 (m, 1H), 2.05 (s, 3H). MS (ESI) m/e [M + 1]⁺ 383. B4

N-(4′-((6-sulfamoylpyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 13.09 (s, 1H), 10.74 (s, 1H), 9.70 (s, 1H), 8.85 - 8.80 (m, 2H), 8.20 - 8.15 (m, 1H), 8.01 -7.91 (m, 2H), 7.50 - 7.45 (m, 2H), 7.38 (s, 1H), 7.35 (s, 2H), 2.18 (s, 3H). MS (ESI) m/e [M + 1]⁺ 385. B5

N-(4′-((6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.97 (s, 1H), 10.57 (s, 1H), 9.24 (s, 1H), 8.90 - 8.80 (m, 2H), 8.27 (s, 1H), 8.15 - 8.10 (m, 1H), 8.05 - 7.95 (m, 2H), 7.60 - 7.50 (m, 1H), 7.48 - 7.35 (m, 2H), 3.47 (s, 3H), 2.13 (s, 3H). MS (ESI) m/e [M + 1]⁺ 384. B6

N-(4′-((4-(2-methoxyethoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.71 (s, 1H), 10.54 (s, 1H), 9.15 (s, 1H), 8.82 (d, J = 3.6 Hz, 1H), 8.77 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.99 (t, J = 7.7 Hz, 1H), 7.50 - 7.42 (m, 1H), 7.11 (s, 1H), 6.91 (s, 1H), 4.38 - 4.30 (m, 2H), 3.74 - 3.66 (m, 2H), 3.44 (s, 3H), 3.32 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M + 1]⁺ 458. B7

N-(4′-((4-(2-hydroxyethoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.67 (s, 1H), 10.54 (s, 1H), 9.15 (s, 1H), 8.82 - 8.81 (m, 1H), 8.76 (s, 1H), 8.10 (d, J = 7.9 Hz, 1H), 7.99 (t, J = 7.3 Hz, 1H), 7.48 - 7.42 (m, 1H), 7.11 (s, 1H), 6.90 (s, 1H), 5.02 - 4.95 (m, 1H), 4.26 - 4.19 (m, 2H), 3.79 - 3.72 (m, 2H), 3.44 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M + 1]⁺ 444. B8

N-(4-(methoxymethyl)-4′-((6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.94 (s, 1H), 10.58 (s, 1H), 9.22 (s, 1H), 8.76 - 8.72 (m, 2H), 7.99 - 7.95 (m, 2H), 7.55 - 7.53 (m, 1H), 7.46 - 7.30 (m, 2H), 4.55 (s, 2H), 3.45 (s, 3H), 3.36 (s, 3H), 2.11 (s, 3H). MS (ESI) m/e [M + 1]⁺ 428. B9

N-(4-(2-hydroxypropan-2-yl)- 4′-((3- (methylsulfonyl)phenyl)amino)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.52 (s, 1H), 10.53 (s, 1H), 8.69 (s, 1H), 8.63 (d, J = 4.5 Hz, 1H), 8.18 (s, 1H), 8.03 (s, 1H), 7.81 (s, 1H), 7.63 - 7.58 (m, 3H), 7.48, (d, J = 4.5 Hz, 1H), 5.36 (s, 1H), 3.28 (s, 3H), 2.07 (s, 3H), 1.48 (s, 6H). MS (ESI) m/e [M + 1]⁺ 441. B10

N-(4-(2-hydroxypropan-2-yl)- 4′-((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.89 (s, 1H), 10.56 (s, 1H), 9.24 (s, 1H), 8.78 (s, 1H), 8.72 (d, J = 4.5 Hz, 1H), 8.08 (s, 1H), 7.54 (d, J = 4.5 Hz, 1H), 7.43 (s, 1H), 7.22 (s, 1H), 5.39 (s, 1H), 3.45 (s, 3H), 2.42 (s, 3H), 2.13 (s, 3H), 1.50 (s, 6H). MS (ESI) m/e [M + 1]⁺ 456. B11

N-(4′-((3- (methylsulfonyl)phenyl)amino)- 5-morpholino-[2,3′-bipyridin]- 6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.61 (s, 1H), 10.50 (s, 1H), 8.61 (s, 1H), 8.42 (s, 1H), 8.16 - 8.03 (m, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.80 (s, 1H), 7.69 - 7.51 (m, 4H), 3.81 - 3.73 (m, 4H), 3.29 (s, 3H), 3.27 - 3.22 (m, 4H), 2.07 (s, 3H). MS (ESI) m/e [M + 1]⁺ 468. B12

N-(5-(2,2- dimethylmorpholino)-4′-((6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 13.16 (s, 1H), 10.49 (s, 1H), 9.19 (s, 1H), 8.69 (s, 1H), 8.47 (s, 1H), 8.19 - 7.85 (m, 2H), 7.52 (d, J = 7.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 1H), 3.78 (d, J = 3.5 Hz, 2H), 3.46 (s, 3H), 3.22 (s, 2H), 3.12 (s, 2H), 2.09 (s, 3H), 1.23 (s, 6H). MS (ESI) m/e [M + 1]⁺ 497. B13

N-(4′-((3- methoxyphenyl)amino)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.44 (s, 1H), 10.40 (s, 1H), 8.70 - 8.69 (m, 1H), 8.65 (s, 1H), 8.15 (s, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.42 - 7.37 (m, 1H), 7.28 (t, J = 8.0 Hz, 1H), 6.91 (s, 1H), 6.85 (d, J = 7.5 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 3.78 (s, 3H), 2.06 (s, 3H). MS (ESI) m/e [M + 1]⁺ 335. B14

N-(4′-((3- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.51 (s, 1H), 10.50 (s, 1H), 9.11 (s, 1H), 8.73 (s, 1H), 8.69 - 8.66 (m, 1H), 8.55 - 8.52 (m, 1H), 8.23 (d, J = 7.1 Hz, 1H), 8.04 (d, J = 7.6 Hz, 1H), 8.05 - 7.95 (m, 1H), 7.44 - 7.39 (m, 1H), 7.26 - 7.20 (m, 1H), 3.36 (s, 3H), 2.10 (s, 3H). MS (ESI) m/e [M + 1]⁺ 384. B15

N-(4′-((2- (methylsulfonyl)phenyl)amino)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.14 (s, 1H), 10.52 (s, 1H), 8.77 (s, 1H), 8.60 - 8.59 (m, 1H), 8.21 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.98 - 7.93 (m, 2H), 7.73 - 7.65 (m, 2H), 7.42 - 7.36 (m, 1H), 7.33 - 7.27 (m, 1H), 3.24 (s, 3H), 2.06 (s, 3H). MS (ESI) m/e [M + 1]⁺ 383. B16

N-(5-(2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)- 4′-((4-isopropoxy-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.76 (s, 1H), 10.41 (s, 1H), 9.09 (s, 1H), 8.64 (s, 1H), 8.25 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.07 (s, 1H), 6.79 (s, 1H), 4.94 - 4.91 (m, 1H), 4.75 - 4.70 (m, 2H), 3.81 - 3.79 (m, 1H), 3.71 - 3.70 (m, 1H), 3.60 - 3.58 (m, 1H), 3.44 (s, 3H), 3.14 - 3.11 (m, 1H), 2.11 (s, 3H), 1.98 - 1.90 (m, 2H), 1.33 (d, J = 8.0 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 539. B17

N-(4-chloro-5-(2- hydroxypropan-2-yl)-4′-((6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.77 (s, 1H), 10.61 (s, 1H), 9.23 (s, 1H), 9.11 (s, 1H), 8.85 (s, 1H), 8.21 (s, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.57 (d, J = 7.3 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 5.63 (s, 1H), 3.47 (s, 3H), 2.13 (s, 3H), 1.66 (s, 6H). MS (ESI) m/e [M + 1]⁺ 476. B18

N-(4′-((4-isopropoxy-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2- (methoxymethyl)morpholino)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.79 (s, 1H), 10.44 (s, 1H), 9.12 (s, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.07 (s, 1H), 6.82 (s, 1H), 5.03 - 4.77 (m, 1H), 4.01 - 3.98 (m, 1H), 3.82 - 3.61 (m, 4H), 3.46 - 3.44 (m, 5H), 3.32 (s, 3H), 2.86 - 2.80 (m, 1H), 2.65 - 2.59 (m, 1H), 2.11 (s, 3H), 1.33 (d, J = 8.0 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 571. B19

N4′-(3- (methylsulfonyl)phenyl)-[2,3′- bipyridine]-4′,6′-diamine MS (ESI) m/e [M + 1]⁺ 341. B20

N-(4′-((3- (methylsulfonyl)phenyl)amino)- [2,3′-bipyridin]-6′- yl)cyclopropanecarboxamide MS (ESI) m/e [M + 1]⁺ 409. B21

(S)-N-(4′-((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)-5-((tetrahydrofuran- 3-yl)oxy)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.61 (s, 1H), 10.58 (s, 1H), 9.15 (s, 1H), 8.53 (s, 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.61 (s, 1H), 7.55 - 7.45 (m, 2H), 7.24 (s, 1H), 5.23 - 5.20 (m, 1H), 3.92 - 3.88 (m, 3H), 3.85 - 3.80 (m, 1H), 3.47 (s, 3H), 2.42 (s, 3H), 2.35 - 2.30 (m, 1H), 2.12 (s, 3H), 2.10 - 2.05 (m, 1H). MS (ESI) m/e [M + 1]⁺ 484. B22

N-(4′-((4-(2-hydroxyethoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-((tetrahydrofuran- 3-yl)oxy)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.35 (s, 1H), 10.50 (s, 1H), 9.13 (s, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.10 (s, 1H), 6.87 (s, 1H), 5.23 - 5.20 (m, 1H), 4.98 (s, 1H), 4.25 - 4.22 (m, 2H), 3.95 - 3.75 (m, 6H), 3.43 (s, 3H), 2.33 - 2.28 (m, 1H), 2.12 (s, 3H), 2.08 - 2.05 (m, 1H). MS (ESI) m/e [M + 1]⁺ 530. B23

N-(4′-((6- (methylsulfonyl)pyridin-2- yl)amino)-5-((tetrahydrofuran- 3-yl)oxy)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.64 (s, 1H), 10.51 (s, 1H), 9.21 (s, 1H), 8.72 (s, 1H), 8.51 (s, 1H), 8.07 (d, J = 7.4 Hz, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 5.23 - 5.20 (m, 1H), 3.92 - 3.88 (m, 3H), 3.85 - 3.80 (m, 1H), 3.47 (s, 3H), 2.35 - 2.30 (m, 1H), 2.12 (s, 3H), 2.10 - 2.05 (m, 1H). MS (ESI) m/e [M + 1]⁺ 470. B24

N-(5-(8-oxa-3- azabicyclo[3.2.1]octan-3-yl)-4′- ((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide MS (ESI) m/e [M + 1]⁺ 509. B25

N-(5-(2,5- dimethylmorpholino)-4′-((4- methyl-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamid MS (ESI) m/e [M + 1]⁺ 511.

Example C1: Synthesis of N-(5-(cis-2,6-dimethylmorpholino)-4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

Step 1: (cis)-4-(6-bromopyridin-3-yl)-2,6-dimethylmorpholine

A mixture of 2-bromo-5-iodopyridine (20 g, 70.4 mmol), (Cis)-2,6-dimethylmorpholine (8.9 g, 77.5 mmol, 1.1 eq), Pd₂(dba)₃ (3.22 g, 3.52 mmol, 0.05 eq), Xant-Phos (2 g, 3.52 mmol, 0.05 eq) and t-BuONa (13.5 g, 140.8 mmol, 2 eq) in toluene (300 mL) was stirred at 80° C. under N₂ for 2 hrs. The reaction mixture was cooled, filtered and the filtrate was concentrated and the residue was purified by column chromatography (PE:EA=20: 1-10:1) to give the product (16 g, 84%) as a brown solid. MS (ESI) m/e [M+1]⁺=271.

Step 2: 6′-chloro-5-(Cis-2,6-dimethylmorpholino)-[2,3′-bipyridin]-4′-amine

To a solution of cis-4-(6-bromopyridin-3-yl)-2,6-dimethylmorpholine (13.6 g, 50.4 mmol) in dioxane/H₂O (400 mL/100 mL) were added 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (15.4, 60.4 mmol), Pd(dppf)Cl₂ (3.7 g, 5.04 mmol) and K₂CO₃ (10.4 g, 75.6 mmol), the resulting mixture was stirred at 100° C. for 2 h under nitrogen atmosphere. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with water (500 mL). The resulting solution was extracted with EA (500 mL×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (MeOH/DCM=0-5%) to give 6′-chloro-5-(Cis-2,6-dimethylmorpholino)-[2,3′-bipyridin]-4′-amine (18 g, crude). MS (ESI) m/e [M+1]⁺ 319.

Step 3: N-(4′-amino-5-(Cis-2,6-dimethylmorpholino)-[2,3′-bipyridin]-6′-yl)acetamide

To a solution of 6′-chloro-5-(cis-2,6-dimethylmorpholino)-[2,3′-bipyridin]-4′-amine (18 g, 56.6 mmol) in 1,4-dioxane (250 mL) were added acetamide (16.7 g, 283 mmol), Pd₂(dba)₃ (5.2 g, 5.7 mmol), XantPhos (6.6 g, 11.4 mmol) and Cs₂CO₃ (37.2 g, 114 mmol), the resulting mixture was stirred at 130° C. for 4 h under nitrogen atmosphere. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with water (20 mL). The resulting solution was extracted with EA (30 mL×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (MeOH/DCM=0-7%) to give N-(4′-amino-5-(cis-2,6-dimethylmorpholino)-[2,3′-bipyridin]-6′-yl)acetamide (12.54 g, 65% yield). MS (ESI) m/e [M+1]⁺ 342.

Step 4: N-(5-(Cis-2,6-dimethylmorpholino)-4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

To a mixture of N-(4′-amino-5-(Cis-2,6-dimethylmorpholino)-[2,3′-bipyridin]-6′-yl)acetamide (50 mg, 0.17 mmol), 2-bromo-4-methyl-6-(methylsulfonyl)pyridine (52 mg, 0.21 mmol), Pd₂dba₃ (16 mg, 0.017 mmol), BINAP (11 mg, 0.017 mmol) and Cs₂CO₃ (111 mg, 0.34 mmol) in dioxane (10 mL) was stirred at 130° C. for 4 h. The mixture was filtrated and the filtrate as concentrated to give the residue and purified by Prep-TLC (MeOH/DCM=1:20) to afford N-(5-(Cis-2,6-dimethylmorpholino)-4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide (38 mg, 510% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H), 10.45 (s, 1H), 9.23 (s, 1H), 8.72 (s, 1H), 8.51 (s, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.42 (s, 1H), 7.20 (s, 1H), 3.80-3.74 (m, 4H), 3.46 (s, 3H), 2.45-2.40 (m, 2H), 2.35 (s, 3H), 2.11 (s, 3H), 1.20 (d, J=6.0 Hz, 6H). MS (ESI) m/e [M+1]⁺ 511.

Example C9: Synthesis of N-(5-(cis-2,6-dimethylmorpholino)-4′-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of N-(4′-amino-5-(cis-2,6-dimethylmorpholino)-[2,3′-bipyridin]-6′-yl)acetamide (1.20 g, 3.52 mmol), 2-bromo-4-methoxy-6-(methylsulfonyl)pyridine (1.15 g, 4.22 mmol), Pd₂(dba)₃ (320 mg, 0.35 mmol), BINAP (218 mg, 0.35 mmol) and Cs₂CO₃ (2.28 g, 7.04 mmol) in 1,4-Dioxane (50 mL) was stirred at 130° C. for 4 hr under nitrogen atmosphere. The reaction mixture was filtered out and the filtrate was concentrated, the residue was purified by combi-flash (MeOH/DCM=7:93) to give the crude product as brown oil, then slurry with ACN (50 mL) at RT for 30 min to give the solid by filtration and dried in vacuum drying oven to give the product (1.3 g, 70% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.83 (s, 1H), 10.46 (s, 1H), 9.11 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 7.96 (d, J=9.1 Hz, 1H), 7.57 (d, J=9.1 Hz, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 3.97 (s, 3H), 3.79-3.73 (m, 4H), 3.44 (s, 3H), 2.40 (t, J=11.0 Hz, 2H), 2.11 (s, 3H), 1.19 (d, J=6.0 Hz, 6H). MS (ESI) m/e [M+1]⁺ 527.

Example C17: Synthesis of N-(5-((cis)-2,6-dimethylmorpholino)-4′-((4-(methoxy-d3)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of N-(4′-amino-5-(cis-2,6-dimethylmorpholino)-[2,3′-bipyridin]-6′-yl)acetamide (2.1 g, 6.16 mmol), 2-bromo-4-(methoxy-d3)-6-(methylsulfonyl)pyridine (2.0 g, 7.39 mmol), Pd₂(dba)₃ (568 mg, 0.62 mmol), BINAP (386 mg, 0.62 mmol) and Cs₂CO₃ (4.02 g, 12.32 mmol) in 1,4-dioxane (75 mL) was stirred at 130° C. for 4 h under N₂. The solid was filtered out and the filtrate was concentrated, the residue was purified by Prep-TLC (MeOH/DCM=1:20) to give the product (2.03 g, 62% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.82 (s, 1H), 10.46 (s, 1H), 9.11 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 7.96 (d, J=9.1 Hz, 1H), 7.55 (s, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 3.79-3.76 (m, 4H), 3.44 (s, 3H), 2.43-2.37 (m, 2H), 2.11 (s, 3H), 1.19 (d, J=5.3 Hz, 6H). MS (ESI) m/e [M+1]⁺ 530.

Example C18: Synthesis of N-(5-(cis-2,6-dimethylmorpholino)-4′-((4-(1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of N-(4′-amino-5-(cis-2,6-dimethylmorpholino)-[2,3′-bipyridin]-6′-yl)acetamide (60 mg, 0.17 mmol), 2-bromo-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine (62 mg, 0.21 mmol), Pd₂dba₃ (16 mg, 0.02 mmol), BINAP (11 mg, 0.02 mmol) and Cs₂CO₃ (111 mg, 0.34 mmol) in 1,4-dioxane (10 mL) was stirred at 130° C. for 4 h under nitrogen atmosphere. The solid was filtered out and the filtrate was concentrated, the residue was purified by Prep-TLC (MeOH/DCM=1:20) to give the product (40.56 mg, 42% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.99 (s, 1H), 10.46 (s, 1H), 9.21 (s, 1H), 8.71 (s, 1H), 8.49 (s, 1H), 7.98 (d, J=9.0 Hz, 1H), 7.57 (d, J=9.2 Hz, 1H), 7.48 (s, 1H), 7.25 (s, 1H), 4.50-4.49 (m, 1H), 3.77-3.74 (m, 4H), 3.48 (s, 3H), 3.23 (s, 3H), 2.41 (t, J=11.1 Hz, 2H), 2.11 (s, 3H), 1.39 (d, J=6.5 Hz, 3H), 1.20 (d, J=6.0 Hz, 6H). MS (ESI) m/e [M+1]⁺=555.

Example C19: Synthesis of N-(5-((cis)-2,6-dimethylmorpholino)-4′-((4-((R or S)-1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of N-(4′-amino-5-((cis)-2,6-dimethylmorpholino)-[2,3′-bipyridin]-6′-yl)acetamide (50 mg, 0.147 mmol), (R or S) 2-bromo-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine (44 mg, 0.176 mmol) (faster peak from example BB60, step 5), Pd₂(dba)₃ (13 mg, 0.0147 mmol), BINAP (18 mg, 0.0294 mmol) and Cs₂CO₃ (72 mg, 0.221 mmol) in 1,4-dioxane (6 mL) was stirred at 130° C. for 4 hr under nitrogen atmosphere. The reaction was cooled to room temperature, filtered and the filtration was concentrated under vacuum. The residue was purified with Prep-TLC (DCM/MeOH=20:1) to afford the product (33 mg, 40%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.01 (s, 1H), 10.49 (s, 1H), 9.21 (s, 1H), 8.71 (s, 1H), 8.50 (s, 1H), 7.99 (d, J=8.9 Hz, 1H), 7.58 (d, J=8.9 Hz, 1H), 7.49 (s, 1H), 7.26 (s, 1H), 4.53-4.43 (m, 1H), 3.84-3.70 (m, 4H), 3.49 (s, 3H), 3.23 (s, 3H), 2.41 (t, J=10.9 Hz, 2H), 2.12 (s, 3H), 1.39 (d, J=5.9 Hz, 3H), 1.20 (d, J=5.4 Hz, 6H). MS (ESI) m/e [M+1]⁺ 555.

Example C20: Synthesis of N-(5-((cis)-2,6-dimethylmorpholino)-4′-((4-((R or S)-1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

A solution of N-(4′-amino-5-(cis-2,6-dimethylmorpholino)-[2,3′-bipyridin]-6′-yl)acetamide (60 mg, 0.18 mmol), (S or R)-2-bromo-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine (slower peak from example BB60, step 5) (62 mg, 0.21 mmol), Pd₂(dba)₃ (33 mg, 0.036 mmol), Xantphos (41.7 mg, 0.072 mmol) and Cs₂CO₃ (117.4 mg, 0.36 mmol) in dioxane (3 mL) was stirred at 130° C. for 4 hr under nitrogen atmosphere. The reaction was cooled to room temperature, filtered and the filtration was concentrated under vacuum. The residue was purified with Prep-TLC (DCM/MeOH=15:1) to afford the product (35.83 mg, 35.89%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.00 (s, 1H), 10.47 (s, 1H), 9.22 (s, 1H), 8.71 (s, 1H), 8.50 (s, 1H), 7.99 (d, J=9.0 Hz, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.48 (s, 1H), 7.26 (s, 1H), 4.53-4.45 (m, 1H), 3.84-3.67 (m, 4H), 3.49 (s, 3H), 3.23 (s, 3H), 2.41 (t, J=11.1 Hz, 2H), 2.11 (s, 3H), 1.39 (d, J=6.3 Hz, 3H), 1.20 (d, J=6.0 Hz, 6H). MS (ESI) m/e [M+1]⁺ 555.

Example C21: Synthesis of N-(5-(cis-2,6-dimethylmorpholino)-4′-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of N-(4′-amino-5-(cis-2,6-dimethylmorpholino)-[2,3′-bipyridin]-6′-yl)acetamide (60 mg, 0.17 mmol), 2-bromo-6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridine (66 mg, 0.21 mmol), Pd₂(dba)₃ (16 mg, 0.02 mmol), BINAP (11 mg, 0.02 mmol) and Cs₂CO₃ (111 mg, 0.34 mmol) in 1,4-dioxane (10 mL) was stirred at 130° C. for 4 hr under N₂. The reaction mixture was filtered out and the filtrate was concentrated, the residue was purified by Prep-TLC (MeOH/DCM=1:20) to give the product (47.27 mg, 46% yield). ¹H NMR (400 MHz, DMSO-d₆) 12.97 (s, 1H), 10.46 (s, 1H), 9.20 (s, 1H), 8.70 (s, 1H), 8.52 (s, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.46 (s, 1H), 7.21 (s, 1H), 3.98 (d, J=10.2 Hz, 2H), 3.83-3.70 (m, 4H), 3.47-3.42 (m, 5H), 3.02-2.95 (m, 1H), 2.41 (t, J=11.0 Hz, 2H), 2.11 (s, 3H), 1.76-1.74 (m, 4H), 1.20 (d, J=6.1 Hz, 6H). MS (ESI) m/e [M+1]⁺ 581.

Example C22: Synthesis of N-(5-(cis-2,6-dimethylmorpholino)-4′-((6-(methylsulfonyl)pyrazin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of N-(4′-amino-5-(cis-2,6-dimethylmorpholino)-[2,3′-bipyridin]-6′-yl)acetamide (60 mg, 0.17 mmol), 2-bromo-6-(methylsulfonyl)pyrazine (49 mg, 0.21 mmol), Pd₂(dba)₃ (16 mg, 0.02 mmol), BINAP (11 mg, 0.02 mmol) and Cs₂CO₃ (111 mg, 0.34 mmol) in 1,4-Dioxane (10 mL) was stirred at 130° C. for 4 hr under N₂ atmosphere. The reaction mixture was filtered out and the filtrate was concentrated, the residue was purified by Prep-TLC (MeOH/DCM=1:20) to give the product (27.37 mg, 31% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 14.00 (s, 1H), 10.50 (s, 1H), 9.29 (s, 1H), 8.78-8.75 (m, 2H), 8.55-8.50 (m, 2H), 8.00 (s, 1H), 7.55 (s, 1H), 3.75-3.69 (m, 4H), 3.53 (s, 3H), 2.37 (t, J=11.0 Hz, 2H), 2.08 (s, 3H), 1.15 (d, J=6.1 Hz, 6H). MS (ESI) m/e [M+1]⁺ 498.

Example C23: Synthesis of compound N-(5-(cis-2,6-dimethylmorpholino)-4′-((4-((S)-3-methylmorpholino)-6-(methylsulfon-yl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)ace-tamide

N-(4′-amino-5-(cis-2,6-dimethylmorpholino)-[2,3′-bipyridin]-6′-yl)aceta-mide (50 mg, 0.15 mmol), (S)-4-(2-chloro-6-(methylsulfonyl)pyridin-4-yl)-3-methyl-morpholine (47 mg, 0.16 mmol), Pd₂dba₃ (13.4 mg, 0.02 mmol), BINAP (18.3 mg, 0.03 mmol) and Cs₂CO₃ (72 mg, 0.22 mmol) were added into 1,4-dioxane (10 mL). The resulting mixture was degassed with nitrogen and stirred at 130° C. for 2 hr. After cooled to room temperature, the solid was filtered out. The filtration was concentrated under vacuum. The residue was purified with Prep-TLC (DCM/MeOH=20/1) to give product (63.39 mg, yield: 72.7%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.28 (s, 1H), 10.41 (s, 1H), 9.00 (s, 1H), 8.62 (s, 1H), 8.46 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.05 (s, 1H), 6.53 (s, 1H), 4.15-4.12 (m, 1H), 3.97 (d, J=12.0 Hz, 1H), 3.88-3.57 (m, 7H), 3.52 (t, J=11.6 Hz, 1H), 3.38 (s, 3H), 3.17 (t, J=11.6 Hz, 1H), 2.39 (t, J=11.0 Hz, 2H), 2.10 (s, 3H), 1.27-1.07 (m, 9H). MS (ESI) m/e [M+1]⁺ 596.

Example C24: Synthesis of compound N-(5-(cis-2,6-dimethylmorpholino)-4′-((4-((R)-3-methylmorpholino)-6-(methylsulfon-yl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)ace-tamide

N-(4′-amino-5-(cis-2,6-dimethylmorpholino)-[2,3′-bipyridin]-6′-yl)aceta-mide (50 mg, 0.15 mmol), (R)-4-(2-chloro-6-(methylsulfonyl)pyridin-4-yl)-3-methyl-morpholine (47 mg, 0.16 mmol), Pd₂dba₃ (13.4 mg, 0.02 mmol), BINAP (18.3 mg, 0.03 mmol) and Cs₂CO₃ (72 mg, 0.22 mmol) were added into 1,4-dioxane (10 mL). The resulting mixture was degassed with nitrogen and stirred at 130° C. for 2 hr. After cooled to room temperature, the solid was filtered out. The filtration was concentrated under vacuum. The residue was purified with Prep-TLC (DCM/MeOH=20/1) to give the product (53.8 mg, yield: 61.7). ¹H NMR (400 MHz, DMSO-d₆) δ 12.27 (s, 1H), 10.40 (s, 1H), 8.99 (s, 1H), 8.62 (s, 1H), 8.46 (s, 8H), 7.92 (d, J=8.6 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.04 (s, 1H), 6.52 (s, 1H), 4.15-4.12 (m, 1H), 3.96 (d, J=10.4 Hz, 1H), 3.78-3.71 (m, 5H), 3.67-3.59 (m, 2H), 3.52 (t, J=11.4 Hz, 1H), 3.37 (s, 3H), 3.16 (t, J=11.4 Hz, 1H), 2.39 (t, J=11.1 Hz, 2H), 2.09 (s, 3H), 1.24-1.08 (in, 9H). MS (ESI) m/e [M+1](596.

The following Examples were prepared in a similar manner to the product Example C1:

¹H NMR and LC /MS Example Compound Chemical Name m/z (M + 1) C2

N-(5-((cis)-2,6- dimethylmorpholino)-4′-((6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 13.23 (s, 1H), 10.48 (s, 1H), 9.20 (s, 1H), 8.71 (s, 1H), 8.48 (d, J = 2.9 Hz, 1H), 7.97-7.94 (m, 2H), 7.57 - 7.52 (m, 2H), 7.36 (d, J = 8.4 Hz, 1H), 3.78 - 3.70 (m, 4H), 3.46 (s, 3H), 2.38 (t, J = 11.1 Hz, 2H), 2.10 (s, 3H), 1.17 (d, J = 6.2 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 497. C3

N-(5-((cis)-2,6- dimethylmorpholino)-4′-((3- (methylsulfonyl)phenyl)amino)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.65 (s, 1H), 10.44 (s, 1H), 8.62 (s, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.79 (s, 1H), 7.68-7.50 (m, 4H), 3.78 - 3.72 (m, 4H), 3.29 (s, 3H), 2.37 (t, J = 11.0 Hz, 2H), 2.06 (s, 3H), 1.17 (d, J = 5.8 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 496. C4

N-(5-((cis)-2,6- dimethylmorpholino)-4′-((4- isopropoxy-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.80 (s, 1H), 10.44 (s, 1H), 9.11 (s, 1H), 8.68 (s, 1H), 8.51 (s, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 6.3 Hz, 1H), 7.08 (s, 1H), 6.80 (s, 1H), 4.95 - 4.92 (m, 1H), 3.79 - 3.73 (m, 4H), 3.44 (s, 3H), 2.40 (t, J = 10.9 Hz, 2H), 2.11 (s, 3H), 1.33 (d, J = 5.9 Hz, 6H), 1.19 (d, J = 5.9 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 555. C5

N-(4′-((4- (cyclopropylmethoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-((cis)-2,6- dimethylmorpholino)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.83 (s, 1H), 10.44 (s, 1H), 9.11 (s, 1H), 8.68 (s, 1H), 8.52 (s, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.10 (s, 1H), 6.82 (s, 1H), 4.10 - 4.05 (m, 2H), 3.83 - 3.65 (m, 4H), 3.44 (s, 3H), 2.45 - 2.35 (m, 2H), 2.11 (s, 3H), 1.28 - 1.22 (m, 1H), 1.19 (d, J = 4.7 Hz, 6H), 0.65 - 0.60 (m, 2H), 0.40 - 0.35 (m, 2H). MS (ESI) m/e [M + 1]⁺ 567. C6

N-(4′-((3- (cyclopropylmethoxy)-5- (methylsulfonyl)phenyl)amino)- 5-((cis)-2,6- dimethylmorpholino)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.64 (s, 1H), 10.43 (s, 1H), 8.61 (s, 1H), 8.41 (s, 1H), 8.20 (s, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.34 (s, 1H), 7.15 (s, 1H), 7.06 (s, 1H), 3.99 - 3.96 (m, 2H), 3.77 - 3.74 (m, 4H), 3.27 (s, 3H), 2.40 - 2.35 (m, 2H), 2.07 (s, 3H), 1.26 - 1.22 (m, 1H), 1.17 (d, J = 6.0 Hz, 6H), 0.62 - 0.58 (m, 2H), 0.38 - 0.32 (m, 2H). MS (ESI) m/e [M + 1]⁺ 566. C7

N-(5-((trans)-2,6- dimethylmorpholino)-4′-((4- methyl-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 13.09 (s, 1H), 10.47 (s, 1H), 9.21 (s, 1H), 8.70 (s, 1H), 8.49 (s, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.42 (s, 1H), 7.20 (s, 1H), 4.11 (d, J = 2.6 Hz, 2H), 3.46 (s, 3H), 3.40 - 3.35 (m, 2H), 3.06 - 3.02 (m, 2H), 2.43 (s, 3H), 2.12 (s, 3H), 1.24 (d, J = 5.8 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 567. C8

N-(5-(Cis-2,6- dimethylmorpholino)-4′-((7- (methylsulfonyl)-2,3-dihydro- [1,4]dioxino[2,3-c]pyridin-5- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 13.26 (s, 1H), 10.44 (s, 1H), 9.39 (s, 1H), 8.70 (s, 1H), 8.37 (s, 1H), 7.97 (d, J = 9.0 Hz, 1H), 7.56 (d, J = 9.0 Hz, 1H), 7.13 (s, 1H), 4.66 - 4.63 (m, 2H), 4.50 - 4.45 (m, 2H), 3.82 - 3.74 (m, 4H), 3.46 (s, 3H), 2.45 - 2.40 (m, 2H), 2.12 (s, 3H), 1.19 (d, J = 6.0 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 555. C9

N-(5-((cis)-2,6- dimethylmorpholino)-4′-((4- methoxy-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide MS (ESI) m/e [M + 1]⁺ 527. C10

N-(5-((cis)-2,6- dimethylmorpholino)-4′-((4- ethoxy-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide MS (ESI) m/e [M + 1]⁺ 541. C11

N-(5-((cis)-2,6- dimethylmorpholino)-4′-((4-(2- methoxyethoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide MS (ESI) m/e [M + 1]⁺ 571. C12

N-(5-((cis)-2,6- dimethylmorpholino)-4′-((4- ((R)-2-hydroxypropoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide MS (ESI) m/e [M + 1]⁺ 571. C13

N-(4′-((4-((R)-sec-butoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-((cis)-2,6- dimethylmorpholino)-[2,3′- bipyridin]-6′-yl)acetamide Molecular Weight: 568.69 MS (ESI) m/e [M + 1]⁺ 569. C14

N-(5-((cis)-2,6- dimethylmorpholino)-4′-((3- methoxy-5- (methylsulfonyl)phenyl)amino)- [2,3′-bipyridin]-6′-yl)acetamide Molecular Weight: 525.62 MS (ESI) m/e [M + 1]⁺ 526. C15

N-(5-((cis)-2,6- dimethylmorpholino)-4′-((3- fluoro-5- (methylsulfonyl)phenyl)amino)- [2,3′-bipyridin]-6′-yl)acetamide MS (ESI) m/e [M + 1]⁺ 514. C16

N-(4′-((3-cyano-5- (methylsulfonyl)phenyl)amino)- 5-((cis)-2,6- dimethylmorpholino)-[2,3′- bipyridin]-6′-yl)acetamide MS (ESI) m/e [M + 1]⁺ 521. C25

N-(5-(cis-2,6-dimethyl- morpholino)-4′-((4-(3-methoxy- azetidin-1-yl)-6- (methylsulfonyl)pyridin -2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide 1H NMR (400 MHz, DMSO- d6) δ 12.39 (s, 1H), 10.49 (s, 1H), 9.04 (s, 1H), 8.70 (s, 1H), 8.53 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 6.70 (s, 1H), 6.20 (s, 1H), 4.45 - 4.42 (m, 1H), 4.32 - 4.30 (m, 2H), 3.97 - 3.95 (m, 2H), 3.86 - 3.80 (m, 4H), 3.43 (s, 3H), 3.34 (s, 3H), 2.49 - 2.44 (m, 2H), 2.17 (s, 3H), 1.26 - 1.23 (m, 6H). MS (ESI) m/e [M + 1]+ 582.

Example D1: Synthesis of N-(5-(2-methoxyethoxy)-4′-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

Step 1: 2-bromo-5-(2-methoxyethoxy)pyridine

To a solution of 6-bromopyridin-3-ol (5 g, 28.7 mmol) in THF (50 mL) was added NaH (60% in mineral oil, 1.7 g, 43.1 mmol) one portions at 0° C. and the resulting mixture was stirred at this temperature for 15 mins, then 1-bromo-2-methoxyethane (8 g, 57.5 mmol) was added dropwise at 0° C. and the mixture was stirred at room temperature for 16 h. Upon completion of the reaction, the reaction mixture was poured into H₂O (200 mL) and the resulting mixture was extracted with EA (40 mL×3). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE/EA=20:1 to 5:1) to give 2-bromo-5-(2-methoxyethoxy)pyridine (4.8 g, 72%). MS (ESI) m/e [M+1]⁺ 232.

Step 2: tert-butyl (6′-chloro-5-(2-methoxyethoxy)-[2,3′-bipyridin]-4′-yl)carbamate

A mixture of 2-bromo-5-(2-methoxyethoxy)pyridine (2.5 g, 10.7 mmol), tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (3.6 g, 11.8 mmol), Sn₂Me₆ (5.2 g, 16.1 mmol), Pd(PPh₃)₄ (1.2 g, 1.08 mmol) and Pd(PPh₃)₂Cl₂ (756.1 mg, 1.1 mmol) in 1,4-dioxane (30 mL) was stirred at 110° C. for 16 h under nitrogen atmosphere. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with 20 mL of water. The resulting solution was extracted with EA (40 mL×3) and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE/EA=50:1 to 0:1) to give tert-butyl (6′-chloro-5-(2-methoxyethoxy)-[2,3′-bipyridin]-4′-yl)carbamate (1.2 g, 29%). ¹H NMR (400 MHz, CDCl₃) δ 11.43 (s, 1H), 8.40 (s, 1H), 8.31-8.25 (m, 2H), 7.57 (d, J=8.8 Hz, 1H), 7.33-7.27 (m, 1H), 4.19-4.12 (m, 2H), 3.77-3.60 (m, 2H), 3.36 (s, 3H), 1.42 (s, 9H). MS (ESI) m/e [M+1]⁺ 380.

Step 3: tert-butyl (6′-acetamido-5-(2-methoxyethoxy)-[2,3′-bipyridin]-4′-yl)carbamate

To a solution of tert-butyl (6′-chloro-5-(2-methoxyethoxy)-[2,3′-bipyridin]-4′-yl)carbamate (0.8 g, 2.1 mmol) in 1,4-dioxane (10 mL) were added acetamide (149 mg, 2.5 mmol), Cs₂CO₃ (1.3 g, 4.2 mmol), XantPhos (243 mg, 0.42 mmol) and Pd₂(dba)₃ (192.86 mg, 0.21 mmol), the resulting mixture was stirred at 110° C. for 16 h under nitrogen atmosphere. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with 10 mL of water. The resulting solution was extracted with EA (10 mL×3) and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE/EA=50:1 to 0:1) to give tert-butyl (6′-acetamido-5-(2-methoxyethoxy)-[2,3′-bipyridin]-4′-yl)carbamate (0.5 g, 58%). MS (ESI) m/e [M+1]⁺ 403.

Step 4: N-(4′-amino-5-(2-methoxyethoxy)-[2,3′-bipyridin]-6′-yl)acetamide

To a mixture of tert-butyl (6′-acetamido-5-(2-methoxyethoxy)-[2,3′-bipyridin]-4′-yl)carbamate (0.5 g, 1.2 mmol) in DCM (8 mL) was added TFA (2 mL) and the resulting solution was stirred at room temperature for 3 h. Upon completion of the reaction, the solvent was removed in vacuo and the residue was diluted with water, then aq. NaHCO₃ (50%) was added to adjust the pH value to 10. The resulting mixture was extracted with EA (10 mL×3). The combined organic layers were dried over Na₂SO₄ and concentrated to give N-(4′-amino-5-(2-methoxyethoxy)-[2,3′-bipyridin]-6′-yl)acetamide (275 mg, 73%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.09 (s, 1H), 8.37-8.29 (m, 2H), 7.82 (d, J=9.0 Hz, 1H), 7.50-7.45 (m, 2H), 7.44-7.34 (m, 2H), 4.25-4.18 (m, 2H), 3.70-3.65 (m, 2H), 3.31 (s, 3H), 2.06 (s, 3H). MS(ESI) m/e [M+1]⁺ 303.

Step 5: N-(5-(2-methoxyethoxy)-4′-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

A solution of N-(T-amino-5-(2-methoxyethoxy)-[2,3′-bipyridin]-6′-yl)acetamide (50 mg, 0.17 mmol), 2-bromo-6-(methylsulfonyl)pyridine (60 mg, 0.26 mmol), Pd(dba)₃ (16 mg, 0.017 mmol), BINAP (10 mg, 0.017 mmol), CsCO₃ (110 mg, 0.34 mmol) in 10 ml dioxane was stirred at 120° C. in sealed tube for 2 h, the solution was concentrated and purified by Prep-TLC to give N-(5-(2-methoxyethoxy)-4′-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide (10 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 12.66 (s, 1H), 10.50 (s, 1H), 919 (s, 1H), 8.70 (s, 1H), 8.55-8.51 (m, 1H), 8.05-7.95 (s, 2H), 7.62-7.59 (m, 1H), 7.54-7.52 (m, 1H), 7.38-7.35 (m, 1H), 4.27-4.25 (m, 2H), 3.71-3.68 (m, 2H), 3.45 (s, 3H), 3.31 (s, 3H), 2.10 (s, 3H). MS (ESI) m/e [M+1]⁺ 458.

The following Examples were prepared in a similar manner to the product Example D1:

¹H NMR and LC /MS Example Compound Chemical Name m/z (M + 1) D2

N-(5-(2- methoxyethoxy)-4′- ((3- (methylsulfonyl)phenyl) amino)-[2,3′- bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.21 (s, 1H), 10.48 (s, 1H), 8.60 (s, 1H), 8.44 (s, 1H), 8.15 (s, 1H), 7.99 (d, J = 9.1 Hz, 1H), 7.81 (s, 1H), 7.61-7.58 (m, 4H), 4.25 - 4.24 (m, 2H), 3.70 - 3.69 (m, 2H), 3.32 (s, 3H), 3.29 (s, 3H), 2.07 (s, 3H). MS (ESI) m/e [M + 1]⁺ 457. D3

N-(5-(2- methoxyethoxy)-4′- ((3-(methylsulfonyl)- 5- (trifluoromethyl)phenyl) amino)-[2,3′- bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.17 (s, 1H), 10.53 (s, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 8.21 (s, 1H), 8.06 (s, 1H), 7.94 (d, J = 8.2 Hz, 2H), 7.76 (s, 1H), 7.57 (d, J = 8.9 Hz, 1H), 4.25 - 4.20 (m, 2H), 3.70 - 3.68 (m, 2H), 3.38 (s, 3H), 3.32 (s, 3H), 2.08 (s, 3H). MS (ESI) m/e [M + 1]⁺ 525. D4

N-(5-(2- methoxyethoxy)-4′- ((4-methyl-6- (methylsulfonyl)pyridin- 2-yl)amino)-[2,3′- bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.67 (s, 1H), 10.54 (s, 1H), 9.20 (s, 1H), 8.71 (s, 1H), 8.56 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.44 (s, 1H), 7.24 (d, J = 10.3 Hz, 2H), 4.29 - 4.22 (m, 2H), 3.72 - 3.70 (m, 2H), 3.46 (s, 3H), 3.34 (s, 3H), 2.42 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M + 1]⁺ 472. D5

N-(4′-((4-methoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(2- methoxyethoxy)-[2,3′- bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.39 (s, 1H), 10.51 (s, 1H), 9.12 (s, 1H), 8.68 (s, 1H), 8.56 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.10 (s, 1H), 6.87 (s, 1H), 4.28 - 4.25 (m, 2H), 3.96 (s, 3H), 3.75 - 3.70 (m, 2H), 3.44 (s, 3H), 3.34 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M + 1]⁺ 488. D6

N-(4′-((4-isopropoxy- 6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(2- methoxyethoxy)-[2,3′- bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.36 (s, 1H), 10.50 (s, 1H), 9.12 (s, 1H), 8.67 (s, 1H), 8.56 (s, 1H), 8.03 (d, J = 9.1 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.06 (s, 1H), 6.83 (s, 1H), 4.95 - 4.91 (m, 1H), 4.30 - 4.25 (m, 2H), 3.75 - 3.71 (m, 2H), 3.43 (s, 3H), 3.34 (s, 3H), 2.11 (s, 3H), 1.33 (d, J = 5.4 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 516. D7

(R)-N-(5-(2- methoxyethoxy)-4′- ((4-(2- methoxypropoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-[2,3′- bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.41 (s, 1H), 10.52 (s, 1H), 9.12 (s, 1H), 8.68 (s, 1H), 8.57 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.11 (s, 1H), 6.88 (s, 1H), 4.30 - 4.25 (m, 2H), 4.20 - 4.15 (m, 2H), 3.72 (s, 3H), 3.44 (s, 3H), 3.35 - 3.28 (m, 6H), 2.12 (s, 3H), 1.19 (d, J = 5.6 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 546. D8

N-(5-(2- methoxyethoxy)-4′- ((4-(2- methoxyethoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-[2,3′- bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.45 (s, 1H), 10.49 (s, 1H), 9.13 (s, 1H), 8.68 (s, 1H), 8.56 (s, 1H), 8.03 (d, J = 8.9 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.11 (s, 1H), 6.87 (s, 1H), 4.33 - 4.28 (m, 4H), 3.75 - 3.70 (m, 4H), 3.44 (s, 3H), 3.33 (s, 3H), 3.32 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M + 1]⁺ 532. D9

N-(4′-((4-ethoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(2- methoxyethoxy)-[2,3′- bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.38 (s, 1H), 10.48 (s, 1H), 9.11 (s, 1H), 8.67 (s, 1H), 8.56 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.08 (s, 1H), 6.84 (s, 1H), 4.28 - 4.24 (m, 4H), 3.75 - 3.70 (m, 2H), 3.43 (s, 3H), 3.34 (s, 3H), 2.11 (s, 3H), 1.38 (t, J = 6.5 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 502. D10

N-(4′-((3- (cyclopropylmethoxy)- 5- (methylsulfonyl)phenyl) amino)-5-(2- methoxyethoxy)-[2,3′- bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.18 (s, 1H), 10.45 (s, 1H), 8.59 (s, 1H), 8.45 (s, 1H), 8.18 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.16 (s, 1H), 7.06 (s, 1H), 4.25 - 4.20 (m, 2H), 3.95 - 3.93 (m, 2H), 3.70 - 3.65 (m, 2H), 3.27 (s, 3H), 2.07 (s, 3H), 1.25 - 1.20 (m, 1H), 0.60 - 0.55 (m, 2H), 0.35 - 0.30 (m, 2H). MS (ESI) m/e [M + 1]⁺ 527. D11

N-(4′-((4- (cyclopropylmethoxy)- 6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(2- methoxyethoxy)-[2,3′- bipyridin]-6′- yl)acetamide MS (ESI) m/e [M + 1]⁺ 528.

Example E1: Synthesis of N-(5-(methoxymethyl)-4′-((3-(methylsulfonyl) phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

Step 1: 2-bromo-5-(methoxymethyl)pyridine

A solution of 2-bromo-5-(bromomethyl) pyridine (10 g, 39.85 mmol), NaOMe (9.6 mL, 51.8 mmol) in MeOH (150 mL) was stirred at RT overnight. The solvent was removed in vacuo and the residue was extracted between EA and H₂O. The organic layer was dried over Na₂SO₄. The organic layer was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE/EA=5:1) to give the desired product 2-bromo-5-(methoxymethyl) pyridine (7.8 g, 96.9% yield). MS (ESI) m/e [M+1]⁺ 202.

Step 2: tert-butyl (6′-chloro-5-(methoxymethyl)-[2,3′-bipyridin]-6⁴′-yl) carbamate

A mixture of 2-bromo-5-(methoxymethyl)pyridine (3 g, 14.84 mmol), Sn₂Me₆ (5.4 g, 16.48 mmol) and Pd(PPh₃)₄ (1.9 g, 1.65 mmol) in dioxane (50 mL) was stirred at 100° C. under N₂ overnight. The mixture was cooled to RT and then tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (4.8 g, 15.6 mmol) and Pd(PPh₃)₂Cl₂ (1.2 g, 1.75 mmol) in dioxane (40 mL) was added under N₂. The mixture was stirred at 100° C. for 10 h under nitrogen atmosphere. After cooled to room temperature, the mixture was diluted with KF—H₂O (50 mL) and extracted with EA (100 mL×2). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE/EA=10:1 to 5:1) to give tert-butyl (6′-chloro-5-(methoxymethyl)-[2,3′-bipyridin]-4′-yl)carbamate (930 mg, 17.9%). MS (ESI) m/e [M+1]⁺ 250.

Step 3: N-(4′-amino-5-(methoxymethyl)-[2,3′-bipyridin]-6′-yl) acetamide TFA salt

A solution of tert-butyl (6′-chloro-5-(methoxymethyl)-[2,3′-bipyridin]-4′-yl) carbamate (580 mg, 1.56 mmol) in DCM (4 mL) was added TFA (2 mL). The mixture was stirred at RT for 5 h. The solvent was removed, and the crude was used in the next step without further purification (400 mg, TFA salt). MS (ESI) m/e [M+1]⁺ 273.

Step 4: N-(5-(methoxymethyl)-4′-((3-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

05761 A solution of N-(4′-amino-5-(methoxymethyl)-[2,3′-bipyridin]-6′-yl) acetamide TFA salt (100 mg, 0.27 mmol), 1-bromo-3-(methylsulfonyl)benzene (174 mg, 0.74 mmol), Cs₂CO₃ (479.8 mg, 1.47 mmol), Xant-phos Pd G3 (70.2 mg, 0.074 mmol) and Xant-phos (85.2 mg, 0.15 mmol) in dioxane (3 mL) was stirred at 130′° C. under N₂ overnight. The mixture was filtered and the filtrate as concentrated to give the crude residue which was purified by Prep-TLC (MeOH/DCM=1:10) to afford N-(5-(Cis-2,6-dimethylmorpholino)-4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide (45.9 mg, 39.9% yield). ¹H NMR (400 MHz, DMSO-d6) δ11.48 (s, 1H), 10.50 (s, 1H), 8.68 (d, J=7.9 Hz, 2H), 8.19 (s, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.83 (s, 1H), 7.64 (s, 2H), 7.62-7.58 (m, 1H), 4.51 (s, 2H), 3.28 (s, 3H), 2.07 (s, 3H). MS (ESI) m/e [M+1]⁺ 427.

¹H NMR and LC /MS Example Compound Chemical Name m/z (M + 1) E2

N-(5-(methoxymethyl)- 4′-((4-methyl-6- (methylsulfonyl)pyridin- 2-yl)amino)-[2,3′- bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.94 (s, 1H), 10.54 (s, 1H), 9.25 (s, 1H), 8.85 - 8.75 (m, 2H), 8.12 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.27 (s, 1H), 4.55 (s, 2H), 3.46 (s, 3H), 3.37 (s, 3H), 2.42 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M + 1]⁺ 442. E3

(R)-N-(5- (methoxymethyl)-4′-((4- (2-methoxypropoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-[2,3′- bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.69 (s, 1H), 10.55 (s, 1H), 9.16 (s, 1H), 8.80 (s, 1H), 8.77 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.11 (s, 1H), 6.93 (s, 1H), 4.54 (s, 2H), 4.25 - 4.12 (m, 2H), 3.71 (s, 1H), 3.44 (s, 3H), 3.37 (s, 3H), 2.12 (s, 3H), 1.20 (d, J = 6.2 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 516. E4

N-(4′-((4-isopropoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)-5- (methoxymethyl)-[2,3′- bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.62 (s, 1H), 10.54 (s, 1H), 9.14 (s, 1H), δ 8.79 (s, 1H), 8.77 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.06 (s, 1H), 6.88 (s, 1H), 5.01 - 4.83 (m, 1H), 4.54 (s, 2H), 3.43 (s, 3H), 3.37 (s, 3H), 2.12 (s, 3H), 1.33 (d, J = 5.9 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 486. E5

N-(4′-((4-(2- methoxyethoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5- (methoxymethyl)-[2,3′- bipyridin]-6′- yl)acetamide 1H NMR (400 MHz, DMSO- d₆) δ 12.74 (s, 1H), 10.55 (s, 1H), 9.17 (s, 1H), 8.80 (s, 1H), 8.75 (s, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.11 (s, 1H), 6.92 (s, 1H), 4.54 (s, 2H), 4.40 - 4.30 (m, 2H), 3.75 - 3.65 (m, 2H), 3.44 (s, 3H), 3.37 (s, 3H), 3.32 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M + 1]⁺ 502. E6

N-(4′-((4-(2- hydroxyethoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5- (methoxymethyl)-[2,3′- bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.69 (s, 1H), 10.54 (s, 1H), 9.17 (s, 1H), 8.80 (s, 1H), 8.78 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.10 (s, 1H), 6.91 (s, 1H), 4.98 (s, 1H), 4.54 (s, 2H), 4.30 - 4.20 (m, 2H), 3.80 - 3.70 (m, 2H), 3.44 (s, 3H), 3.37 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M + 1]⁺ 488. E7

N-(4′-((4-methoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)-5- (methoxymethyl)-[2,3′- bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.68 (s, 1H), 10.55 (s, 1H), 9.15 (s, 1H), 8.78 (s, 1H), 8.72 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.11 (s, 1H), 6.92 (s, 1H), 4.54 (s, 2H), 3.96 (s, 3H), 3.44 (s, 3H), 3.37 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M + 1]⁺ 458. E8

N-(4′-((4-((1r,3r)-3- hydroxycyclobutoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5- (methoxymethyl)-[2,3′- bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ = 12.56 (s, 1H), 10.54 (s, 1H), 9.12 (s, 1H), 8.76 (s, 2H), 8.09 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 6.99 (s, 1H), 6.73 (s, 1H), 5.28 (d, J = 5.4 Hz, 1H), 5.12 - 5.06 (m, 1H), 4.54 (s, 2H), 4.42 - 4.36 (m, 1H), 3.42 (s, 3H), 3.37 (s, 3H), 2.39 - 2.35 (m, 4H), 2.12 (s, 3H). MS (ESI) m/e [M + 1]⁺ 514. E9

N-(5-(methoxymethyl)- 4′-((4-(methoxymethyl)- 6- (methylsulfonyl)pyridin- 2-yl)amino)-[2,3′- bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.89 (s, 1H), 10.56 (s, 1H), 9.26 (s, 1H), δ 8.79 (s, 1H), 8.77 (s, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.50 (s, 1H), 7.31 (s, 1H), δ 4.56 (s, 2H), 4.55 (s, 2H), 3.48 (s, 3H), 3.39 (s, 2H), 3.37 (s, 2H), 2.13 (s, 3H). MS (ESI) m/e [M + 1]⁺ 472.

Example F1: Synthesis of N-(4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of N-(4′-amino-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamide (100 mg, 0.34 mmol), 2-bromo-4-methyl-6-(methylsulfonyl)pyridine (100 mg, 0.4 mmol), Pd₂dba₃ (27 mg, 0.03 mmol), BINAP (18 mg, 0.03 mmol) and Cs₂CO₃ (208 mg, 0.64 mmol) in dioxane (6 mL) was stirred at 130° C. under N₂ in a sealed tube for 4 h. The reaction mixture was filtered and the solid was washed with EA (10 mL). The filtrate was concentrated and the residue was purified by prep-TLC (DCM/MeOH=20:1) to give N-(4′-((4-methyl-6-(methyl sulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamide (37 mg, 23%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.42 (s, 1H), 10.61 (s, 1H), 9.26 (s, 1H), 9.20 (s, 1H), 8.84 (s, 1H), 8.32-8.30 (m, 2H), 7.44 (s, 1H), 7.31 (s, 1H), 3.44 (s, 3H), 2.41 (s, 3H), 2.11 (s, 3H). MS (ESI) m/e [M+1]⁺ 466.

Example F17: Synthesis of N-(5-fluoro-4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of N-(4′-amino-5-fluoro-[2,3′-bipyridin]-6′-yl)acetamide (800 mg, 3.25 mmol), 2-bromo-4-methyl-6-(methylsulfonyl)pyridine (976 mg, 3.9 mmol), Pd₂(dba)₃ (297 mg, 0.325 mmol), BINAP (405 mg, 0.65 mmol) and Cs₂CO₃ (1.59 g, 4.875 mmol) in 1,4-dioxane (14 mL) was stirred 130° C. for 3 hr under N₂ atmosphere. The reaction was cooled to room temperature, filtered and the filtration was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM/MeOH=100:1) to afford the product (600 mg, 44%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 1H), 10.53 (s, 1H), 9.20 (s, 1H), 8.80 (s, 1H), 8.71 (s, 1H), 8.16 (d, J=7.3 Hz, 1H), 7.95 (d, J=7.3 Hz, 1H), 7.44 (s, 1H), 7.23 (s, 1H), 3.44 (s, 3H), 2.41 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M+1]⁺ 416.

Example F22: Synthesis of N-(5-fluoro-4′-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

Step 1: 6′-chloro-5-fluoro-[2,3′-bipyridin]-4′-amine

A mixture of 2-bromo-5-fluoropyridine (1.6 g, 9.09 mmol), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (2.54 g, 10 mmol), Pd(dppf)Cl₂ (664 mg, 0.909 mmol) and K₂CO3 (1.88 g, 13.64 mmol) in 1,4-dioxane (50 mL) and H₂O (5 mL) was stirred at 100° C. for 2 hr. The reaction was cooled to room temperature and diluted with EA, washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography (EA/PE=1:3) to give the product (1.9 g). MS (ESI) m/e [M+1]⁺ 224.

Step 2: N-(4′-amino-5-fluoro-[2,3′-bipyridin]-6′-yl)acetamide

A mixture 6′-chloro-5-fluoro-[2,3′-bipyridin]-4′-amine (1.4 g, 6.25 mmol), acetamide (2.21 g, 37.5 mmol), Pd₂(dba)₃ (572 mg, 0.625 mmol), Xantphos (724 mg, 1.25 mmol) and Cs₂CO₃ (4.08 g, 12.5 mmol) in 1,4-dioxane (20 mL) was degassed with nitrogen and heated to 130° C. in a sealed tube stirring overnight. The reaction was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM/MeOH=50:1) to give the product (1.4 g, crude). MS (ESI) m/e [M+1]⁺ 247.

Step 3: N-(5-fluoro-4′-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of N-(4′-amino-5-fluoro-[2,3′-bipyridin]-6′-yl)acetamide (1.5 g, 6.07 mmol), 2-bromo-4-methoxy-6-(methylsulfonyl)pyridine (1.78 g, 6.68 mmol), Pd₂(dba)₃ (555 mg, 0.607 mmol), BINAP (765 mg, 1.214 mmol) and Cs₂CO₃ (3.96 g, 12.14 mmol) in 1,4-dioxane (30 mL) was degassed with nitrogen and heated to 130° C. in a sealed tube stirring for 3 hr. The reaction was cooled to room temperature, filtered and the filtration was concentrated under vacuum. The residue was purification by column flash on silica gel eluted with DCM/MeOH (100:1) to afford the desired product as a light yellow solid. It was then washed with 10 mL of MeCN to give the product (27 mg, 30%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.82 (s, 1H), 10.54 (s, 1H), 9.10 (s, 1H), 8.81 (s, 1H), 8.68 (s, 1H), 8.20-8.06 (m, 1H), 7.95-7.90 (m, 1H), 7.11 (s, 1H), 6.90 (s, 1H), 3.95 (s, 3H), 3.42 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M+1]⁺ 432.

Example F23: Synthesis of N-(4′-((3,4-dimethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-fluoro-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of N-(4′-amino-5-fluoro-[2,3′-bipyridin]-6′-yl)acetamide (40 mg, 0.163 mmol), 2-bromo-3,4-dimethoxy-6-(methylsulfonyl)pyridine (53 mg, 0.179 mmol), Pd₂(dba)₃ (15 mg, 0.0163 mmol), BINAP (20 mg, 0.0326 mmol) and Cs₂CO₃ (106 mg, 0.326 mmol) in 1,4-dioxane (6 mL) was degassed with nitrogen and heated to 130° C. in a sealed tube stirring for 4 hr. The reaction was cooled to room temperature, filtered and the filtration was concentrated under vacuum. The residue was applied onto Prep-TLC with (DCM/MeOH=20:1) to afford the product (40 mg, 30%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.64 (s, 1H), 10.53 (s, 1H), 9.40 (s, 1H), 8.82 (s, 1H), 8.75 (s, 1H), 8.21 (d, J=4.8 Hz, 1H), 7.99 (d, J=6.4 Hz, 1H), 7.38 (s, 1H), 4.02 (s, 3H), 3.97 (s, 3H), 3.50 (s, 3H), 2.13 (s, 3H). MS (ESI) m/e [M+1]⁺ 462.

Example F24: Synthesis of N-(5-fluoro-4′-((4-(methoxy-d3)-6-(methylsulfonyl)pyridine-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of N-(4′-amino-5-fluoro-[2,3′-bipyridin]-6′-yl)acetamide 40 mg, 0.163 mmol), 2-bromo-4-(methoxy-d3)-6-(methylsulfonyl)pyridine (48 mg, 0.179 mmol), Pd₂(dba)₃ (15 mg, 0.0163 mmol), BINAP (20 mg, 0.0326 mmol) and Cs₂CO₃ (132 mg, 0.326 mmol) in 1,4-dioxane (6 mL) was degassed with nitrogen and heated to 130° C. in a sealed tube stirring for 3 hr. The reaction was cooled to room temperature, filtered and the filtration was concentrated under vacuum. The residue was applied onto Prep-TLC (DCM/MeOH=20:1) to afford the product (30 mg, 30%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.81 (s, 1H), 10.54 (s, 1H), 9.10 (s, 1H), 8.81 (s, 1H), 8.68 (s, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.11 (s, 1H), 6.89 (s, 1H), 3.42 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M+1]⁺ 435.

Example F25: Synthesis of N-(4′-((4-cyclopropyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-fluoro-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of N-(4′-amino-5-fluoro-[2,3′-bipyridin]-6′-yl)acetamide (50 mg, 0.203 mmol), 2-chloro-4-cyclopropyl-6-(methylsulfonyl)pyridine (57 mg, 0.244 mmol), Pd₂(dba)₃ (19 mg, 0.0203 mmol), BINAP (25 mg, 0.0406 mmol) and Cs₂CO₃ (132 mg, 0.406 mmol) in 1,4-dioxane (6 mL) was degassed with nitrogen and heated to 130° C. in a sealed tube stirring for 4 hr. The reaction was cooled to room temperature, filtered and the filtration was concentrated under vacuum. The residue was applied onto Prep-TLC with (DCM/MeOH=20:1) to afford the product (23 mg, 25%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (s, 11), 10.49 (s, 1H), 9.06 (s, 1H), 8.77 (s, 1H), 8.64 (s, 1H), 8.10-8.08 (m, 8H), 7.95-7.90 (m, 1H), 7.22 (s, 1H), 7.02 (s, 1H), 3.37 (s, 3H), 2.07 (s, 4H), 1.96-1.94 (m, 1H), 1.12-1.05 (m, 2H), 0.95-0.88 (m, 2H). MS (ESI) m/e [M+]⁺ 442.

¹H NMRand LC /MS Example Compound Chemical Name m/z (M + 1) F2

N-(4′-((3- (methylsulfonyl)phenyl)amino)- 5-(trifluoromethyl)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 10.99 (s, 1H), 10.56 (s, 1H), 9.07 (s, 1H), 8.72 (s, 1H), 8.28 (s, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.81 (s, 1H), 7.65 -7.61 (m, 3H), 3.26 (s, 3H), 2.05 (s, 3H). MS (ESI) m/e [M + 1]⁺ 451. F3

N-(4′-((3-methyl-5- (methylsulfonyl)phenyl)amino)- 5-(trifluoromethyl)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.02 (s, 1H), 10.56 (s, 1H), 9.09 (s, 1H), 8.74 (s, 1H), 8.41 - 8.12 (m, 3H), 7.64 (s, 1H), 7.46 (s, 2H), 3.26 (s, 3H), 2.41 (s, 3H), 2.08 (s, 3H). MS (ESI) m/e [M + 1]⁺ 465. F4

N-(4′-((3-cyano-5- (methylsulfonyl)phenyl)amino)- 5-(trifluoromethyl)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.06 (s, 1H), 10.67 (s, 1H), 9.08 (s, 1H), 8.75 (s, 1H), 8.31 (s, 1H), 8.21 (s, 2H), 8.07 (s, 2H), 7.98 (s, 1H), 2.10 (s, 3H). MS (ESI) m/e [M + 1]⁺ 476. F5

N-(4′-((3-((trans)-3- hydroxycyclobutoxy)-5- (methylsulfonyl)phenyl)amino)- 5-(trifluoromethyl)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 10.92 (s, 1H), 10.56 (s, 1H), 9.09 (s, 1H), 8.72 (s, 1H), 8.29 - 8.20 (m, 3H), 7.40 (s, 1H), 7.03 (s, 1H), 6.98 (s, 1H), 5.25 - 5.19 (m, 1H), 4.95 - 4.90 (m, 1H), 4.37 - 4.32 (m, 1H), 3.27 (s, 3H), 2.35 - 2.30 (m, 4H), 2.08 (s, 3H). MS (ESI) m/e [M + 1]⁺ 537. F6

N-(4′-((3- (cyclopropylmethoxy)-5- (methylsulfonyl)phenyl)amino)- 5-(trifluoromethyl)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.01 (s, 1H), 10.56 (s, 1H), 9.10 (s, 1H), 8.73 (s, 1H), 8.32 - 8.22 (m, 3H), 7.39 (s, 1H), 7.19 (s, 1H), 7.10 (s, 1H), 3.95 (d, J = 6.6 Hz, 2H), 3.27 (s, 3H), 2.08 (s, 3H), 1.30 - 1.24 (m, 1H), 0.59 - 0.58 (m, 2H), 0.35 - 0.30 (m, 2H). MS (ESI) m/e [M + 1]⁺ 521. F7

N-(4′-((3-(2-hydroxyethoxy)-5- (methylsulfonyl)phenyl)amino)- 5-(trifluoromethyl)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.00 (s, 1H), 10.57 (s, 1H), 9.10 (s, 1H), 8.74 (s, 1H), 8.30 - 8.26 (m, 3H), 7.41 (s, 1H), 7.21 (s, 1H), 7.12 (s, 1H), 4.93 (s, 1H), 4.11 (s, 2H), 3.74 (s, 2H), 3.28 (s, 3H), 2.09 (s, 3H). MS (ESI) m/e [M + 1]⁺ 511. F8

N-(4′-((3-(2-methoxyethoxy)-5- (methylsulfonyl)phenyl)amino)- 5-(trifluoromethyl)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.02 (s, 1H), 10.58 (s, 1H), 9.10 (s, 1H), 8.74 (s, 1H), 8.34 - 8.21 (m, 3H), 7.41 (s, 1H), 7.22 (s, 1H), 7.12 (s, 1H), 4.23 (s, 2H), 3.69 (s, 2H), 3.28 (s, 3H), 2.09 (s, 3H). MS (ESI) m/e [M + 1]⁺ 525. F9

N-(4′-((4-isopropoxy-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(trifluoromethyl)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.13 (s, 1H), 10.62 (s, 1H), 9.20 - 9.15 (m, 2H), 8.83 (s, 1H), 8.40 - 8.23 (m, 2H), 7.09 (s, 1H), 6.93 (s, 1H), 4.92 (s, 1H), 3.43 (s, 3H), 2.13 (s, 3H), 1.33 (d, J = 5.0 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 510. F10

N-(4′-((4-ethoxy-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(trifluoromethyl)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.21 (s, 1H), 10.62 (s, 1H), 9.22 (s, 1H), 9.19 (s, 1H), 8.83 (s, 1H), 8.35 - 8.32 (m, 2H), 7.11 (s, 1H), 6.94 (s, 1H), 4.28 - 4.24 (m, 2H), 3.44 (s, 3H), 2.13 (s, 3H), 1.40 - 1.38 (m, 3H). MS (ESI) m/e [M + 1]⁺ 496. F11

N-(4′-((4-(2-methoxyethoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(trifluoromethyl)- [2,3′-bipyridin]-6′- yl)acetamidecarboxamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.27 (s, 1H), 10.63 (s, 1H), 9.25 - 9.20 (m, 2H), 8.85 (s, 1H), 8.34 (d, J = 9.4 Hz, 2H), 7.14 (s, 1H), 6.98 (s, 1H), 4.34 (s, 2H), 3.71 (s, 2H), 3.44 (s, 3H), 2.13 (s, 3H). MS (ESI) m/e [M + 1]⁺ 526. F12

N-(4′-((4-(2-hydroxyethoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(trifluoromethyl)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d6) δ 12.19 (s, 1H), 10.62 (s, 1H), 9.25 - 9.20 (m, 2H), 8.83 (s, 1H), 8.42 - 8.24 (m, 2H), 7.13 (s, 1H), 6.96 (s, 1H), 4.98 (s, 1H), 4.22 (s, 2H), 3.77 (s, 2H), 3.44 (s, 3H), 2.13 (s, 3H). MS (ESI) m/e [M + 1]⁺ 512. F13

N-(5-fluoro-4′-((3- (methylsulfonyl)-5- (trifluoromethyl)phenyl)amino)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 10.68 (s, 1H), 10.58 (s, 1H), 8.71 (s, 1H), 8.60 (s, 1H), 8.21 (s, 1H), 8.05 (s, 2H), 7.99 - 7.90 (m, 2H), 7.77 (s, 1H), 3.37 (s, 3H), 2.09 (s, 3H). MS (ESI) m/e [M + 1]⁺ 460. F14

N-(5-fluoro-4′-((3-isopropoxy- 5- (methylsulfonyl)phenyl)amino)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 10.69 (s, 1H), 10.49 (s, 1H), 8.71 (s, 1H), 8.60 (s, 1H), 8.18 (s, 1H), 8.07 (d, J = 7.2 Hz, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.35 (s, 1H), 7.11 (s, 1H), 7.05 (s, 1H), 4.73 (s, 1H), 3.27 (s, 3H), 2.07 (s, 3H), 1.30 (d, J = 5.1 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 459. F15

N-(5-fluoro-4′-((3-((trans)-3- hydroxycyclobutoxy)-5- (methylsulfonyl)phenyl)amino)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 10.64 (s, 1H), 10.49 (s, 1H), 8.71 (s, 1H), 8.59 (s, 1H), 8.18 (s, 1H), 8.07 (d, J = 7.2 Hz, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.37 (s, 1H), 7.00 (s, 1H), 6.95 (s, 1H), 5.20 (s, 1H), 4.94 - 4.90 (m, 1H), 4.37 - 4.32 (m, 1H), 3.26 (s, 3H), 2.35 - 2.30 (m, 4H), 2.08 (s, 3H). MS (ESI) m/e [M + 1]⁺ 487. F16

N-(5-fluoro-4′-((4-(2- methoxyethoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.91 (s, 1H), 10.55 (s, 1H), 9.12 (s, 1H), 8.81 (s, 1H), 8.70 (s, 1H), 8.18 - 8.10 (m, 1H), 7.99 - 7.90 (m, 1H), 7.11 (s, 1H), 6.90 (s, 1H), 4.36 - 4.28 (m, 2H), 3.74 - 3.66 (m, 2H), 3.42 (s, 3H), 3.32 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M + 1]⁺ 476. F18

N-(5-fluoro-4′-((4-isopropoxy- 6-(methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.79 (s, 1H), 10.53 (s, 1H), 9.10 (s, 1H), 8.82 (s, 1H), 8.68 (s, 1H), 8.12 - 7.94 (m, 2H), 7.06 (s, 1H), 6.86 (s, 1H), 4.90 - 4.88 (m, 1H), 3.42 (s, 3H), 2.12 (s, 3H), 1.33 (d, J = 5.2 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 460. F19

N-(4′-((4-ethoxy-6- (methylsulfonyl)pyridin-2- yl)amino)-5-fluoro-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.85 (s, 1H), 10.55 (s, 1H), 9.12 (s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.13 -7.95 (m, 2H), 7.08 (s, 1H), 6.87 (s, 1H), 4.26 - 4.23 (m, 2H), 3.42 (s, 3H), 2.12 (s, 3H), 1.37 (t, J = 6.3 Hz , 3H). MS (ESI) m/e [M + 1]⁺ 446. F20

N-(4′-((4-methoxy-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(trifluoromethyl)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.16 (s, 1H), 10.61 (s, 1H), 9.21(s, 1H), 9.17 (s, 1H), 8.83 (s, 1H), 8.36 - 8.29 (m, 2H), 7.13 (s, 1H), 6.95 (s, 1H), 3.96 (s, 3H), 3.43 (s, 3H), 2.13 (s, 3H). MS (ESI) m/e [M + 1]⁺ 482. F21

(S)-N-(4′-((4-(2- hydroxypropoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(trifluoromethyl)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.10 (s, 1H), 10.60 (s, 1H), 9.22 (s, 1H), 9.18 (s, 1H), 8.82 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.15 - 7.13 (m, 1H), 6.99 - 6.95 (m, 1H), 4.98 (s, 1H), 4.05 - 4.00 (m, 2H), 3.43 (s, 3H), 2.13 (s, 3H), 1.99 - 1.95 (m, 1H), 1.20 - 1.15 (m, 3H). MS (ESI) m/e [M + 1]⁺ 526.

Example G1: Synthesis of N-(4′-((3-(methylsulfonyl)phenyl)amino)-5-(3-oxomorpholino)-[2,3′-bipyridin]-6′-yl)acetamide

Step 1: 2-(2-chloroethoxy)acetyl chloride

A mixture of 2-(2-chloroethoxy)acetic acid (1.0 g, 7.2 mmol) and DMF (0.1 mL) in SOCl₂ (20 mL) was heated at 70° C. for 3 h. After cooled to room temperature, the solvent was removed in vacuo to give 2-(2-chloroethoxy)acetyl chloride (1.1 g, crude).

Step 2: N-(6-bromopyridin-3-yl)-2-(2-chloroethoxy)acetamide

To a mixture of 2-(2-chloroethoxy)acetyl chloride (1.1 g, 7.0 mmol) in THF (20 mL) was added 6-bromopyridin-3-amine (1.2 g, 7.0 mmol) and Et₃N (2.1 g, 21.0 mmol) and the resulting mixture was stirred at room temperature for 12 h. Upon completion of the reaction, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE/EA=2:1 to 1:1) to give N-(6-bromopyridin-3-yl)-2-(2-chloroethoxy)acetamide (1.5 g, 72.8%). ¹H NMR (400 MHz, CDCl₃) δ 8.59 (s, 1H), 8.48 (s, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 4.18 (s, 2H), 3.94-3.89 (m, 2H), 3.80-3.76 (m, 2H). MS (ESI) m/e [M+1]⁺ 293.

Step 3: 4-(6-bromopyridin-3-yl)morpholin-3-one

To a solution of N-(6-bromopyridin-3-yl)-2-(2-chloroethoxy)acetamide (1.5 g, 5.1 mmol) in DMF (20 mL) was added NaH (60% in mineral oil, 307 mg, 7.7 mmol) portionwise at 0° C. Then the mixture was stirred at room temperature for 2 h. Upon completion of the reaction, water was added and the resulting mixture was extracted with EA (50 mL×3). The combined organic layers were concentrated under vacuum to give 4-(6-bromopyridin-3-yl)morpholin-3-one (1.1 g, 84.6%). ¹H NMR (400 MHz, CDCl₃) δ 8.35-8.30 (m, 1H), 7.61 (s, 1H), 7.49-7.42 (m, 1H), 4.28 (s, 2H), 4.02-3.97 (m, 1H), 4.02-3.97 (m, 1H), 3.76-3.71 (m, 1H), 3.76-3.71 (m, 1H). MS (ESI) m/e [M+1]⁺ 412.

Step 4: 4-(6′-amino-4′-chloro-[2,3′-bipyridin]-5-yl)morpholin-3-one

A mixture of 4-(6-bromopyridin-3-yl)morpholin-3-one (200 mg, 673.4 umol), 4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (340 mg, 1.4 mmol), Pd(dppf)Cl₂ (49 mg, 67.3 umol), and Na₂CO₃ (142 mg, 1.4 mmol) in ACN (10 mL)/H₂O (2 mL) was heated at 120° C. under microwave irradiation for 20 mins under nitrogen atmosphere. After cooled to room temperature, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography (EA/MeOH=100:1 to 30:1) to give 4-(6′-amino-4′-chloro-[2,3′-bipyridin]-5-yl)morpholin-3-one (120 mg, 58.5%). MS (ESI) m/e [M+1]⁺ 305.

Step 5: N-(4′-chloro-5-(3-oxomorpholino)-[2,3′-bipyridin]-6′-yl)acetamide

To a mixture of 4-(6′-amino-4′-chloro-[2,3′-bipyridin]-5-yl)morpholin-3-one (340 mg, 1.1 mmol) in pyridine (10 mL) was added AcCl (105 mg, 1.3 mmol) dropwise at 0° C. Then the mixture was stirred at room temperature for 12 h. Upon completion of the reaction, water (0.2 mL) was added and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (EA/MeOH=100:1 to 30:1) to give N-(4′-chloro-5-(3-oxomorpholino)-[2,3′-bipyridin]-6′-yl)acetamide (150 mg, 39%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H), 8.88 (s, 1H), 8.61 (s, 1H), 8.37 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.89 (d, J=8.4 Hz, 1H), 4.34 (s, 2H), 4.13-4.05 (m, 2H), 3.97-3.89 (m, 2H), 2.21 (s, 3H). MS (ESI) m/e [M+1]⁺ 347.

Step 6: N-(4′-((3-(methylsulfonyl)phenyl)amino)-5-(3-oxomorpholino)-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of N-(4′-chloro-5-(3-oxomorpholino)-[2,3′-bipyridin]-6′-yl)acetamide (150 mg, 432 umol), 3-(methylsulfonyl)aniline (147 mg, 865 umol), Pd₂(dba)₃ (39 mg, 43 umol), Xant-Phos (25 mg, 43 umol), and Cs₂CO₃ (421 mg, 1.3 mmol) in dioxane (5 mL) was heated at 110° C. for 12 h under nitrogen atmosphere. After cooled to room temperature, the solvent was removed in vacuo and the residue was purified by neutral prep-HPLC (column: Phenomenex Gemini-NX 150×30 mm×5 um; phase: A-H₂O (10 mM NH₄HCO₃); B-ACN; B %: 10%-40% in 20 min) to give N-(4′-((3-(methylsulfonyl)phenyl)amino)-5-(3-oxomorpholino)-[2,3′-bipyridin]-6′-yl)acetamide (5.6 mg, 2.7%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.31 (s, 1H), 10.52 (s, 1H), 8.84 (s, 1H), 8.71 (s, 1H), 8.20 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.84 (s, 1H), 7.69-7.64 (m, 2H), 7.63-7.58 (m, 1H), 4.29 (s, 2H), 4.08-4.01 (m, 2H), 3.91-3.84 (m, 2H), 3.30 (s, 3H), 2.09 (s, 3H). MS (ESI) m/e [M+1]⁺ 482.

Example G2: Synthesis of N-(4′-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3-oxomorpholino)-[2,3′-bipyridin]-6′-yl)acetamide

Step 1: tert-butyl (6′-chloro-5-(3-oxomorpholino)-[2,3′-bipyridin]-4′-yl)carbamate

A mixture of tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (3.0 g, 9.8 mmol), 4-(6-bromopyridin-3-yl)morpholin-3-one (2.9 g, 9.8 mmol), Pd(PPh₃)₂Cl₂ (688 mg, 977 umol), Pd(PPh₃)₄ (1.1 g, 977 umol), and Sn₂Me₆ (4.8 g, 14.7 mmol) in 1,4-dioxane (30 mL) was heated at 100° C. under nitrogen atmosphere for 12 h. After cooled to room temperature, the mixture was quenched with 10% KF solution (100 mL) and extracted with EA (100 mL×3). The combined organic layer was washed with brine (100 mL), dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE/EA=1:1 to 1:2) to give tert-butyl (6′-chloro-5-(3-oxomorpholino)-[2,3′-bipyridin]-4′-yl)carbamate (1.1 g, 28%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.96 (s, 1H), 8.87 (s, 1H), 8.86-8.83 (m, 1H), 8.28 (s, 1H), 8.24-8.18 (m, 1H), 8.17-8.10 (m, 1H), 4.29 (s, 2H), 4.08-3.99 (m, 2H), 3.93-3.86 (m, 2H), 1.50 (s, 9H). MS (ESL) m/e [M+1]⁺ 405.

Step 2: tert-butyl (6′-acetamido-5-(3-oxomorpholino)-[2,3′-bipyridin]-4′-yl)carbamate

A mixture of tert-butyl (6′-chloro-5-(3-oxomorpholino)-[2,3′-bipyridin]-4′-yl)carbamate (500 mg, 1.2 mmol), acetamide (146 mg, 2.5 mmol), Pd₂(dba)₃ (113 mg, 123 umol), Xantphos (72 mg, 124 umol) and Cs₂CO₃ (808 mg, 2.5 mmol) in 1,4-dioxane (10 mL) was heated at 110° C. under nitrogen atmosphere for 12 h. After cooled to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (EA/MeOH=100:1 to 30:1) to give tert-butyl (6′-acetamido-5-(3-oxomorpholino)-[2,3′-bipyridin]-4′-yl)carbamate (300 mg, 57%). MS (ESI) m/e [M+1]⁺ 428.

Step 3: N-(4′-amino-5-(3-oxomorpholino)-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of tert-butyl (6′-acetamido-5-(3-oxomorpholino)-[2,3′-bipyridin]-4′-yl)carbamate (300 mg, 703 umol) in HCl/EA (20 mL, v:v=1:9) was stirred at room temperature for 2 h. Upon completion of the reaction, the solvent was removed in vacuo and the residue was purified by prep-HPLC [column: Phenomenex Gemini-NX C18 75×30 mm×3 um; liquid phase: [A-10 mM NH₄HCO₃ in H₂O; B-ACN]B %: 5%-45%, 8 min] to give N-(4′-amino-5-(3-oxomorpholino)-[2,3′-bipyridin]-6′-yl)acetamide (98 mg, 43%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.11 (s, 1H), 8.63 (s, 1H), 8.41 (s, 1H), 7.96-7.86 (m, 2H), 7.55-7.45 (m, 3H), 4.22 (s, 2H), 3.99-3.95 (m, 2H), 3.82-3.78 (m, 2H), 2.03 (s, 3H). MS (ESI) m/e [M+1]⁺ 328.

Step 4: N-(4′-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3-oxomorpholino)-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of N-(4′,5-diamino-[2,3′-bipyridin]-6′-yl)acetamide (98 mg, 0.40 mmol), 2-bromo-6-(methylsulfonyl)pyridine (96 mg, 0.41 mmol), Pd₂(dba)₃ (18 mg, 0.02 mmol), BINAP (23 mg, 0.04 mmol) and K₃PO₄ (174 mg, 0.82 mmol) in 1,4-dioxane (10 mL) was heated to 100° C. for 4 h under nitrogen atmosphere. After cooled to room temperature, the mixture was filtrated and the filtrate was concentrated under vacuum. The residue was purified by Prep-TLC (MeOH/DCM=1/15) to afford N-(4′-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3-oxomorpholino)-[2,3′-bipyridin]-6′-yl)acetamide (15 mg, 7.6). ¹H NMR (400 MHz, DMSO-d₆) δ 12.70 (s, 1H), 10.56 (s, 1H), 9.20 (s, 1H), 8.93-8.83 (m, 1H), 8.79 (s, 1H), 8.17 (d, J=8.4 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 8.02-7.95 (m, 1H), 7.54 (s, 1H), 7.45-7.41 (i, 1H), 4.27 (s, 2H), 4.05-4.00 (m, 2H), 3.90-3.82 (m, 2H), 3.45 (s, 3H), 2.11 (s, 3H). MS (ESI) m/e [M+1]⁺ 483.

The following Examples were prepared in a similar manner to the product Examples G2:

¹H NMR and LC /MS Example Compound Chemical Name m/z (M + 1) G3

N-(4′-((4-(2- hydroxyethoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(3- oxomorpholino)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.49 (s, 1H), 10.53 (s, 1H), 9.13 (s, 1H), 8.90 (s, 1H), 8.75 (s, 1H), 8.13 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 8.6 Hz, 1H), 7.08 (s, 1H), 6.87 (s, 1H), 5.02 (s, 1H), 4.27 (s, 2H), 4.25 - 4.15 (m, 2H), 4.05 - 4.00 (m, 2H), 3.90 - 3.82 (m, 2H), 3.80 - 3.70 (m, 2H), 3.41 (s, 3H), 2.10 (s, 3H). MS (ESI) m/e [M + 1]⁺ 543. G4

N-(4′-((4-(2- methoxyethoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(3- oxomorpholino)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.54 (s, 1H), 10.55 (s, 1H), 9.14 (s, 1H), 8.93 - 8.90 (m, 1H), 8.77 (s, 1H), 8.20 - 8.15 (m, 1H), 8.10 - 8.00 (m, 1H), 7.09 (s, 1H), 6.91 (s, 1H), 4.35 - 4.30 (m, 2H), 4.27 (s, 2H), 4.05 - 3.97 (m, 2H), 3.90 - 3.80 (m, 2H), 3.70 - 3.60 (m, 2H), 3.42 (s, 3H), 3.35 (s, 3H), 2.10 (s, 3H). MS (ESI) m/e [M + 1]⁺ 557.

Example H1: Synthesis of N-(5-(2-hydroxypropan-2-yl)-4′-((3-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

Step 1: tert-butyl (6′-chloro-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-4′-yl)carbamate

A mixture of tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (650 mg, 2.1 mmol), 2-(6-bromopyridin-3-yl)propan-2-ol (525 mg, 2.4 mmol), Sn₂Me₆ (1.0 g, 3.1 mmol), Pd(PPh₃)₄ (244.2 mg, 211.3 umol) and Pd(PPh₃)₂Cl₂ in 1,4-dioxane (10 mL) was heated to 105° C. for 12 h under nitrogen atmosphere. After cooled to room temperature, the mixture was washed with KF (5 mL) and filtered. The organic layer was concentrated under vacuum and the residue was purified by silica gel column chromatography (PE/EA=10:1) to give tert-butyl (6′-chloro-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-4′-yl)carbamate (0.4 g, 52%). ¹H NMR (400 MHz, CDCl₃) δ 11.93 (s, 1H), 8.82 (s, 1H), 8.59 (s, 1H), 8.45 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H) 1.68 (s, 6H), 1.56 (s, 9H). MS (ESI) m/e [M+1]⁺ 364.

Step 2: tert-butyl (6′-acetamido-5-(2-hydroxypropan-2-yl)-[2,3-bipyridin]-4′-yl)carbamate

A mixture of tert-butyl (6′-chloro-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-4′-yl)carbamate (0.3 g, 824 umol), acetamide (97 mg, 1.6 mmol), Cs₂CO₃ (841 mg, 2.4 mmol), Xantphos (95 mg, 165 umol), Pd₂(dba)₃ (151 mg, 165 umol) in 1,4-dioxane (50 mL) was gradually warmed up to 90° C. and stirred at this temperature for 12 h under nitrogen atmosphere. After cooled to room temperature, the solution was filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE/EA=1/1 to 0/1) to give tert-butyl (6′-acetamido-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-4′-yl)carbamate (0.22 g, 69%). ¹H NMR (400 MHz, CDCl₃) δ 11.81 (s, 1H), 9.15 (s, 1H), 8.79 (s, 1H), 8.50 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.72-7.68 (m, 1H), 2.23 (s, 3H), 1.67 (s, 6H), 1.66-1.69 (m, 1H), 1.56 (s, 9H). MS (ESI) m/e [M+1]⁺ 387.

Step 3: N-(4′-amino-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of tert-butyl (6′-acetamido-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-4′-yl)carbamate (150 mg, 388 umol) in TFA (1 mL) and DCM (2 mL) was stirred at 15° C. for 2 h under nitrogen atmosphere. Upon completion of the reaction, the solvent was removed in vacuo to give N-(4′-amino-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide (0.1 g, crude). It was used directly for next step without further purification. MS (ESI) m/e [M+1]⁺ 287.

Step 4: N-(5-(2-hydroxypropan-2-yl)-4′-((3-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of N-(4′-amino-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide (0.1 g, 349 umol), 1-bromo-3-(methylsulfonyl)benzene (246 mg, 1.1 mmol), Cs₂CO₃ (358 mg, 1.1 mmol), Xantphos (20 mg, 35 umol), Pd₂(dba)₃ (35 mg, 35 umol) in 1,4-dioxane (5 mL) was gradually warmed up to 110° C. and stirred at this temperature for 12 h under nitrogen atmosphere. After cooled to room temperature, the solution was filtered and the filtrate was concentrated under vacuum. The residue was purified by Prep-HPLC (column: Phenomenex Gemini-NX 150×30 mm×5 um; phase: A-H₂O (10 mM NH₄HCO₃); B-ACN; B %: 10%-40% in 20 min) to give N-(5-(2-hydroxypropan-2-yl)-4′-((3-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide (11 mg, 7.1%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 10.47 (s, 1H), 8.81 (s, 1H), 8.69 (s, 1H), 8.18 (s, 1H), 8.00 (s, 2H), 7.82 (s, 1H), 7.66-7.62 (m, 2H), 7.60-7.55 (m, 1H), 5.29 (s, 1H), 3.28 (s, 3H), 2.07 (s, 3H), 1.50 (s, 6H). MS (ESI) m/e [M+1]⁺ 441.

Example H2: Synthesis of N-(5-(2-hydroxypropan-2-yl)-4′-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of N-(4′-amino-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide (400 mg, 1.40 mmol), 2-bromo-4-isopropoxy-6-(methylsulfonyl)pyridine (492 mg, 1.68 mmol), Pd₂(dba)₃ (128 mg, 0.14 mmol), BINAP (88 mg, 0.14 mmol) and Cs₂CO₃ (1.368 g, 4.20 mmol) in dioxane (20 mL) was stirred for 4 h at 130° C. under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (MeOH/DCM=0-10%) to give the crude product. The crude product was suspended in acetonitrile to give N-(5-(2-hydroxypropan-2-yl)-4′-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide (272.5 mg, 39.0%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.82 (s, 1H), 10.50 (s, 1H), 9.11 (s, 1H), 8.90 (s, 1H), 8.75 (s, 1H), 8.05-7.99 (m, 2H), 7.05 (s, 1H), 6.86 (s, 1H), 5.33 (s, 1H), 4.98-4.81 (m, 1H), 3.41 (s, 3H), 2.10 (s, 3H), 1.50 (s, 6H), 1.31 (d, J=4.0 Hz, 6H). MS (ESI) m/e [M+1]⁺ 500.

Example H3: Synthesis of N-(5-(2-hydroxypropan-2-yl)-4′-((3-(methylsulfonyl)-5-(trifluoro methyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

A mixture of N-(4′-amino-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide (100 mg, 0.35 mmol), 1-bromo-3-(methylsulfonyl)-5-(trifluoromethyl)benzene (127 mg, 0.42 mmol), Pd₂(dba)₃ (32 mg, 0.035 mmol), BINAP (22 mg, 0.035 mmol) and Cs₂CO₃ (342 mg, 1.05 mmol) in dioxane (10 mL) was stirred for 16 h at 120° C. under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (MeOH/DCM=0-10%) to give the crude product. The crude product was suspended in acetonitrile to give N-(5-(2-hydroxypropan-2-yl)-4′-((3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide (18.77 mg, 10.5%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 10.50 (s, 1H), 8.76 (s, 1H), 8.64 (s, 1H), 8.17 (s, 1H), 8.03 (s, 1H), 7.92-7.90 (m, 3H), 7.71 (s, 1H), 5.26 (s, 1H), 3.24 (s, 3H), 2.02 (s, 3H), 1.43 (s, 6H). MS (ESI) m/e [M+1]⁺ 509.

Example H43: Synthesis of N-(5-(2-hydroxypropan-2-yl)-4′-((3-isopropoxy-5-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide

A solution of N-(4′-amino-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide (860 mg, 3 mmol), 1-bromo-3-isopropoxy-5-(methylsulfonyl)benzene (1.1 g, 3.6 mmol), Pd₂(dba)₃ (274.7 mg, 0.3 mmol), Xant-phos (347.2 mg, 0.6 mmol) and Cs₂CO₃ (1.96 g, 6 mmol) in dioxane (20 mL) was stirred at 130° C. for 5 hr. The mixture was cooled to RT then filtered. The filtrate was concentrated under reduced pressure to give the crude product and purified by silica gel column chromatography (DCM/MeOH=15:1) to give the desired product (937.6 mg, 62.67%). ¹H NMR (400 MHz, DMSO-d6) δ711.63 (s, 1H), 10.47 (s, 1H), 8.82 (s, 1H), 8.68 (s, 1H), 8.20 (s, 1H), 8.00 (s, 2H), 7.37 (s, 1H), 7.15 (s, 1H), 7.05 (s, 1H), 5.30 (s, 1H), 4.84-4.69 (in, H), 3.32 (s, 3H), 3.28 (s, 3H), 2.08 (s, 3H), 1.50 (s, 6H), 1.31 (d, J=5.9 Hz, 6H). MS (ESI) m/e [M+1]⁺ 499.

The following Examples were prepared in a similar manner to the product Example H1:

¹H NMR and LC /MS Example Compound Chemical Name m/z (M + 1) H4

N-(5-(2-hydroxypropan-2-yl)-4′- ((3-methoxy-5- (methylsulfonyl)phenyl)amino)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 10.48 (s, 1H), 8.80 (s, 1H), 8.67 (s, 1H), 8.22 (s, 1H), 8.04 - 7.92 (m, 2H), 7.36 (s, 1H), 7.22 - 7.21 (m, 1H), 7.07 (s, 1H), 5.30 (s, 1H), 3.86 (s, 3H), 3.27 (s, 3H), 2.06 (s, 3H), 1.48 (s, 6H). MS (ESI) m/e [M + 1]⁺ 471. H5

N-(5-(2-hydroxypropan-2-yl)-4′- ((6-(methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 13.17 (s, 1H), 10.52 (s, 1H), 9.23 (s, 1H), 8.89 (s, 1H), 8.79 (s, 1H), 8.05 - 8.00 (m, 3H), 7.54 (d, J = 7.3 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 5.32 (s, 1H), 3.46 (s, 3H), 2.11 (s, 3H), 1.50 (s, 6H) MS (ESI) m/e [M + 1]⁺ 442. H6

N-(5-(2-hydroxypropan-2-yl)-4′- ((4-(2-methoxyethoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.94 (s, 1H), 10.52 (s, 1H), 9.15 (s, 1H), 8.93 (s, 1H), 8.78 (s, 1H), 8.05 - 8.00 (m, 2H), 7.12 (s, 1H), 6.93 (s, 1H), 5.34 (s, 1H), 4.40 - 4.36 (m, 2H), 3.71 - 3.62 (m, 2H), 3.44 (s, 3H), 2.12 (s, 3H), 1.52 (s, 6H). MS (ESI) m/e [M + 1]⁺ 516. H7

N-(5-(2-hydroxypropan-2-yl)-4′- ((4-(2-methoxypropoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.87 (s, 1H), 10.50 (s, 1H), 9.13 (s, 1H), 8.91 (s, 1H), 8.75 (s, 1H), 8.05 - 7.99 (m, 2H), 7.10 (s, 1H), 6.91 (s, 1H), 5.35 (s, 1H), 4.22 - 4.12 (m, 2H), 3.76 - 3.61 (m, 1H), 3.42 (s, 3H), 3.30 (s, 3H), 2.10 (s, 3H), 1.50 (s, 6H), 1.18 (d, J = 6.3 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 530. H8

N-(4′-((4-(2-hydroxyethoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2-hydroxypropan-2- yl)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.89 (s, 1H), 10.51 (s, 1H), 9.14 (s, 1H), 8.97 - 8.84 (m, 1H), 8.76 (s, 1H), 8.04 - 7.99 (m, 2H), 7.09 (s, 1H), 6.89 (s, 1H), 5.33 (s, 1H), 4.97 - 4.92 (m, 1H), 4.31 - 4.12 (m, 2H), 3.76 - 3.72 (m, 2H), 3.42 (s, 3H), 2.10 (s, 3H), 1.50 (s, 6H). MS (ESI) m/e [M + 1]⁺ 502. H9

N-(5-(2-hydroxypropan-2-yl)-4′- ((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (s, 1H), 10.51 (s, 1H), 9.27 (s, 1H), 8.93 (s, 1H), 8.80 (s, 1H), 8.11 - 8.03 (m, 2H), 7.44 (s, 1H), 7.27 (s, 1H), 5.36 (s, 1H), 3.47 (s, 3H), 2.43 (s, 3H), 2.13 (s, 3H), 1.53 (s, 6H). MS (ESI) m/e [M + 1]⁺ 456. H10

N-(4′-((4-(trans)-3- hydroxycyclobutoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2-hydroxypropan-2- yl)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.77 (s, 1H), 10.49 (s, 1H), 9.09 (s, 1H), 8.89 (s, 1H), 8.74 (s, 1H), 8.02 (s, 2H), 6.97 (s, 1H), 6.72 (s, 1H), 5.32 - 5.27 (m, 2H), 5.07 (s, 1H), 4.38 (s, 1H), 3.41 (s, 3H), 2.35 (s, 4H), 2.10 (s, 3H), 1.50 (s, 6H). MS (ESI) m/e [M + 1]⁺ 528. H11

N-(5-(2-hydroxypropan-2-yl)-4′- ((4-methoxy-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.87 (s, 1H), 10.52 (s, 1H), 9.14 (s, 1H), 8.92 (s, 1H), 8.77 (s, 1H), 8.05 - 8.00 (m, 2H), 7.12 (s, 1H), 6.92 (s, 1H), 5.34 (s, 1H), 3.97 (s, 3H), 3.44 (s, 3H), 2.12 (s, 3H), 1.52 (s, 6H). MS (ESI) m/e [M + 1]⁺ 472. H12

N-(5-(2-hydroxypropan-2-yl)-4′- ((6-(methylsulfonyl)-4-(oxetan-3- ylmethoxy)pyridin-2-yl)amino)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.91 (s, 1H), 10.51 (s, 1H), 9.14 (s, 1H), 8.92 (s, 1H), 8.76 (s, 1H), 8.06 - 7.99 (m, 2H), 7.12 (s, 1H), 6.93 (s, 1H), 5.34 (s, 1H), 4.73 - 4.69 (m, 2H), 4.46 - 4.43 (m, 4H), 3.43 (s, 3H), 3.40 - 3.38 (m, 1H) 2.10 (s, 3H), 1.50 (s, 6H). MS (ESI) m/e [M + 1]⁺ 528. H13

N-(5-(2-hydroxypropan-2-yl)-4′- ((4-(methoxymethyl)-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 13.07 (s, 1H), 10.47 (s, 1H), 9.20 (s, 1H), 8.84 (s, 1H), 8.74 (s, 1H), 7.82 - 7.75 (m, 2H), 7.43 (s, 1H), 7.24 (s, 1H), 5.31 (s, 1H), 4.50 (s, 2H), 3.42 (s, 3H), 3.35 (s, 3H), 2.06 (s, 3H), 1.45 (s, 6H). MS (ESI) m/e [M + 1]⁺ 486. H14

N-(4′-((4-cyano-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2-hydroxypropan-2- yl)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 13.81 (s, 1H), 10.60 (s, 1H), 9.26 (s, 1H), 8.96 (s, 1H), 8.86 (s, 1H), 8.12 (s, 1H), 8.10 (s, 1H), 8.07 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.9 (d, J = 8.0 Hz, 1H), 5.36 (s, 1H), 3.52 (s, 3H), 2.11 (s, 3H), 1.51 (s, 6H). MS (ESI) m/e [M + 1]⁺ 467. H15

N-(5-(2-hydroxypropan-2-yl)-4′- ((3-(2-methoxyethoxy)-5- (methylsulfonyl)phenyl)amino)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.68 (s, 1H), 10.49 (s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.22 (s, 1H), 8.05 - 8.00 (m, 2H), 7.39 (s, 1H), 7.22 (s, 1H), 7.09 (s, 1H), 5.31 (s, 1H), 4.28 - 4.24 (m, 2H), 3.68 - 3.62 (m, 2H), 3.28 (s, 3H), 2.08 (s, 3H), 1.50 (s, 6H). MS (ESI) m/e [M + 1]⁺ 515. H16

N-(5-(2-hydroxypropan-2-yl)-4′- ((3-(methoxymethyl)-5- (methylsulfonyl)phenyl)amino)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.67 (s, 1H), 10.49 (s, 1H), 8.81 (s, 1H), 8.69 (s, 1H), 8.19 (s, 1H), 8.05 - 8.00 (m, 2H), 7.76 (s, 1H), 7.54 (d, J = 8.1 Hz, 2H), 5.31 (s, 1H), 4.52 (s, 2H), 3.36 (s, 3H), 3.29 (s, 3H), 2.08 (s, 3H), 1.50 (s, 6H). MS (ESI) m/e [M + 1]⁺ 485. H17

N-(5-(2-hydroxypropan-2-yl)-4′- ((3-(3-hydroxypyrrolidin-1-yl)-5- (methylsulfonyl)phenyl)amino)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.61 (s, 1H), 10.47 (s, 1H), 8.82 (s, 1H), 8.65 (s, 1H), 8.19 (s, 1H), 8.05 - 8.00 (m, 2H), 6.98 (s, 1H), 6.69 (d, J = 18.3 Hz, 2H), 5.31 (s, 1H), 5.02 (s, 1H), 4.42 (s, 1H), 3.53 - 3.49 (m, 1H), 3.45 - 3.40 (m, 2H), 3.24 (s, 3H), 3.17 (d, J = 10.0 Hz, 1H), 2.08 (s, 4H), 1.96 - 1.93 (m, 1H), 1.50 (s, 6H). MS (ESI) m/e [M + 1]⁺ 526. H18

N-(5-(2-hydroxypropan-2-yl)-4′- ((3-(methylsulfonyl)-5- (trifluoromethoxy)phenyl)amino)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.72 (s, 1H), 10.56 (s, 1H), 8.83 (s, 1H), 8.71 (s, 1H), 8.23 (s, 1H), 8.05 - 8.00 (m, 2H), 7.86 (s, 1H), 7.66 (s, 1H), 7.45 (s, 1H), 5.32 (s, 1H), 3.31 (s, 3H), 2.09 (s, 3H), 1.50 (s, 6H). MS (ESI) m/e [M + 1]⁺ 525. H19

N-(4′-((3-fluoro-5- (methylsulfonyl)phenyl)amino)- 5-(2-hydroxypropan-2-yl)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.74 (s, 1H), 10.54 (s, 1H), 8.82 (s, 1H), 8.71 (s, 1H), 8.24 (s, 1H), 8.05 - 7.99 (m, 2H), 7.67 (s, 1H), 7.55 - 7.50 (m, 1H), 7.40 - 7.36 (m, 1H), 5.31 (s, 1H), 3.34 (s, 3H), 2.09 (s, 3H), 1.50 (s, 6H). MS (ESI) m/e [M + 1]⁺ 459. H20

N-(4′-((3-cyano-5- (methylsulfonyl)phenyl)amino)- 5-(2-hydroxypropan-2-yl)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.79 (s, 1H), 10.57 (s, 1H), 8.82 (s, 1H), 8.72 (s, 1H), 8.21 (s, 1H), 8.09 - 8.05 (m, 2H), 7.99 - 7.95 (m, 2H), 7.94 (s, 1H), 5.30 (s, 1H), 3.36 (s, 3H), 2.10 (s, 3H), 1.50 (s, 6H). MS (ESI) m/e [M + 1]⁺ 466. H21

N-(5-(2-hydroxypropan-2-yl)-4′- ((3-methyl-5- (methylsulfonyl)phenyl)amino)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 10.47 (s, 1H), 8.81 (s, 1H), 8.68 (s, 1H), 8.18 (s, 1H), 8.00 - 7.95 (m, 2H), 7.64 (s, 1H), 7.47 (s, 1H), 7.42 (s, 1H), 5.30 (s, 1H), 3.27 (s, 3H), 2.42 (s, 3H), 2.08 (s, 3H), 1.50 (s, 6H). MS (ESI) m/e [M + 1]⁺ 455. H22

N-(4′-((3-(cyclopropylmethoxy)- 5- (methylsulfonyl)phenyl)amino)- 5-(2-hydroxypropan-2-yl)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 10.48 (s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.22 (s, 1H), 8.00 - 7.94 (m, 2H), 7.38 (s, 1H), 7.20 (s, 1H), 7.07 (s, 1H), 5.30 (s, 1H), 4.00 - 3.95 (m, 2H), 3.32 (s, 3H), 2.08 (s, 3H), 1.50 (s, 6H), 1.29 - 1.25 (m, 1H), 0.65 - 0.59 (m, 2H), 0.36 - 0.31 (m, 2H). MS (ESI) m/e [M + 1]⁺ 511. H23

N-(4′-((3-cyclopropoxy-5- (methylsulfonyl)phenyl)amino)- 5-(2-hydroxypropan-2-yl)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 10.48 (s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.23 (s, 1H), 8.05 - 7.99 (m, 2H), 7.42 (s, 1H), 7.33 (s, 1H), 7.19 (s, 1H), 5.30 (s, 1H), 4.06 - 4.00 (m, 1H), 3.29 (s, 3H), 2.08 (s, 3H), 1.50 (s, 6H), 0.86 - 0.67 (m, 4H). MS (ESI) m/e [M + 1]⁺ 497. H24

N-(5-(2-hydroxypropan-2-yl)-4′- ((3-isopropoxy-5- (methylsulfonyl)phenyl)amino)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.62 (s, 1H), 10.47 (s, 1H), 8.82 (s, 1H), 8.68 (s, 1H), 8.19 (s, 1H), 8.00 - 7.95 (m, 2H), 7.37 (s, 1H), 7.15 (s, 1H), 7.05 (s, 1H), 5.30 (s, 1H), 4.87 - 4.65 (m, 1H), 3.28 (s, 3H), 2.08 (s, 3H), 1.50 (s, 6H), 1.31 (d, J = 4.0 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 499 H25

N-(4′-((3-(difluoromethyl)-5- (methylsulfonyl)phenyl)amino)- 5-(2-hydroxypropan-2-yl)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.71 (s, 1H), 10.52 (s, 1H), 8.82 (s, 1H), 8.71 (s, 1H), 8.22 (s, 1H), 8.00 - 7.95 (m, 3H), 7.82 (s, 1H), 7.72 (s, 1H), 7.28 - 7.00 (m, 1H), 5.30 (s, 1H), 3.35 (s, 3H), 2.08 (s, 3H), 1.50 (s, 6H). MS (ESI) m/e [M + 1]⁺ 491 H26

N-(5-(2-hydroxypropan-2-yl)-4′- ((4-(2-hydroxypropoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.83 (s, 1H), 10.51 (s, 1H), 9.14 (s, 1H), 8.92 (s, 1H), 8.77 (s, 1H), 8.04 - 8.02 (m, 2H), 7.12 (s, 1H), 6.91 (s, 1H), 5.34 (s, 1H), 5.10 (s, 1H), 4.99 - 4.92 (s, 1H), 4.06 - 4.02 (m, 2H), 3.43 (s, 3H), 2.12 (s, 3H), 1.52 (s, 6H), 1.27 - 1.17 (m, 3H). MS (ESI) m/e [M + 1]⁺ 516. H27

N-(5-(2-hydroxypropan-2-yl)-4′- ((6-(methylsulfonyl)-4-(oxetan-3- yloxy)pyridin-2-yl)amino)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.90 (s, 1H), 10.53 (s, 1H), 9.11 (s, 1H), 8.93 (s, 1H), 8.78 (s, 1H), 8.07 - 8.02 (m, 2H), 7.01 (s, 1H), 6.70 (s, 1H), 5.59 (s, 1H), 5.36 (s, 1H), 4.99 - 4.91 (m, 2H ), 4.66 - 4.61 (m, 2H), 3.44 (s, 3H), 2.12 (s, 3H), 1.53 (s, 6H). MS (ESI) m/e [M + 1]⁺ 514. H28

N-(4′-((4-(cis-3- hydroxycyclobutoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2-hydroxypropan-2- yl)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.83 (s, 1H), 10.53 (s, 1H), 9.10 (s, 1H), 8.92 (s, 1H), 8.77 (s, 1H), 8.07 - 8.04 (m, 2H), 7.02 (s, 1H), 6.79 (s, 1H), 5.45 - 5.27 (m, 2H), 4.67 - 4.45 (m, 1H), 3.90 - 3.88 (m, 1H), 3.43 (s, 3H), 2.87 - 2.82 (m, 2H), 2.12 (s, 3H), 1.98 - 1.92 (m, 2H), 1.52 (s, 6H). MS (ESI) m/e [M + 1]⁺ 528. H29

N-(5-(2-hydroxypropan-2-yl)-4′- ((4-(3-methoxycyclobutoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.81 (s, 1H), 10.52 (s, 1H), 9.11 (s, 1H), 8.92 (s, 1H), 8.77 (s, 1H), 8.04 - 8.01 (m, 2H), 7.04 - 7.00 (m, 1H), 6.80 - 6.76 (m, 1H), 5.35 (s, 1H), 5.10 (s, 1H), 4.10 (s, 1H), 3.43 (s, 3H), 3.18 (s, 3H), 2.46 (m, 2H), 2.42 - 2.31 (m, 2H), 2.12 (s, 3H), 1.52 (s, 6H). MS (ESI) m/e [M + 1]⁺ 542. H30

N-(4′-((4-(cyclopropylmethoxy)- 6-(methylsulfonyl)pyridin-2- yl)amino)-5-(2-hydroxypropan-2- yl)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.87 (s, 1H), 10.52 (s, 1H), 9.14 (s, 1H), 8.94 (s, 1H), 8.78 (s, 1H), 8.08 - 8.05 (m, 2H), 7.15 - 7.10 (m, 1H), 6.91 (s, 1H), 5.35 (s, 1H), 4.08 (d, J = 8.0 Hz, 2H), 3.44 (s, 3H), 2.13 (s, 3H), 1.54 (s, 6H), 1.25 - 1.22 (m, 1H), 0.65 - 0.62 (m, 2H), 0.41 - 0.38 (m, 2H). MS (ESI) m/e [M + 1]⁺ 512. H31

N-(4′-((4-cyclobutoxy-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2-hydroxypropan-2- yl)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.80 (s, 1H), 10.51 (s, 1H), 9.10 (s, 1H), 8.91 (s, 1H), 8.77 (s, 1H), 8.08 - 8.02 (m, 2H), 7.02 (s, 1H), 6.78 (s, 1H), 5.34 (s, 1H), 4.99 - 4.92 (m, 1H), 3.43 (s, 3H), 2.49 - 2.42 (m, 2H), 2.16 - 2.11 (m, 5H), 1.85 - 1.80 (m, 1H), 1.75 - 1.69 (m, 1H), 1.52 (s, 6H). MS (ESI) m/e [M + 1]⁺ 512. H32

N-(5-(2-hydroxypropan-2-yl)-4′- ((3-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 13.14 (s, 1H), 10.52 (s, 1H), 9.35 (s, 1H), 8.86 (s, 1H), 8.82 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 5.36 (s, 1H), 3.45 (s, 3H), 2.53 (s, 3H), 2.13 (s, 3H), 1.52 (s, 6H). MS (ESI) m/e [M + 1]⁺ 456. H33

N-(4′-((4-ethoxy-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2-hydroxypropan-2- yl)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.88 (s, 1H), 10.50 (s, 1H), 9.14 (s, 1H), 8.92 (s, 1H), 8.77 (s, 1H), 8.12 - 7.94 (m, 2H), 7.09 (s, 1H), 6.88 - 6.85 (m, 1H), 5.34 (s, 1H), 4.29 - 4.24 (m, 2H), 3.43 (s, 3H), 2.12 (s, 3H), 1.52 (s, 6H), 1.40 - 1.36 (m, 3H). MS (ESI) m/e [M + 1]⁺ 486. H34

N-(4′-((5-fluoro-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2-hydroxypropan-2- yl)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.96 (s, 1H), 10.53 (s, 1H), 8.96 (s, 1H), 8.88 (s, 1H), 8.78 (s, 1H), 8.07 - 7.96 (m, 3H), 7.56 - 7.52 (m, 1H), 5.33 (s, 1H), 3.51 (s, 3H), 2.12 (s, 3H), 1.51 (s, 6H). MS (ESI) m/e [M + 1]⁺ 460. H35

N-(5-(2-hydroxypropan-2-yl)-4′- ((2-methyl-5- (methylsulfonyl)phenyl)amino)- [2,3′-bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.86 (s, 1H), 10.46 (s, 1H), 8.79 - 8.74 (m, 2H), 8.12 - 7.96 (m, 3H), 7.89 (s, 1H), 7.69 - 7.43 (m, 2H), 5.30 (s, 1H), 3.27 (s, 3H), 2.45 (s, 3H), 2.06 (s, 3H), 1.50 (s, 6H). MS (ESI) m/e [M + 1]⁺ 455. H36

N-(4′-((6-(ethylsulfonyl)-4- isopropoxypyridin-2-yl)amino)-5- (2-hydroxypropan-2-yl)-[2,3′- bipyridin]-6′-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.76 (s, 1H), 10.48 (s, 1H), 9.04 (s, 1H), 8.92 (s, 1H), 8.76 (s, 1H), 8.06 - 8.03 (m, 2H), 7.07 (s, 1H), 6.88 (s, 1H), 5.33 (s, 1H), 5.04 - 4.82 (m, 1H), 3.69 - 3.64 (m, 2H), 2.12 (s, 3H), 1.52 (s, 6H), 1.34 (d, J = 4.0 Hz, 6H), 1.19 - 1.16 (m, 3H). MS (ESI) m/e [M + 1]⁺ 514. H37

N-(5-(2-hydroxypropan-2-yl)-4′- ((7-(methylsulfonyl)-2,3-dihydro- [1,4]dioxino[2,3-c]pyridin-5- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 13.40 (s, 1H), 10.50 (s, 1H), 9.42 (s, 1H), 8.81 - 8.80 (m, 2H), 8.10 - 8.03 (m, 2H), 7.15 (s, 1H), 5.34 (s, 1H), 4.62 - 4.51 (m, 4H), 3.46 (s, 3H), 2.13 (s, 3H), 1.53 (s, 6H). MS (ESI) m/e [M + 1]⁺ 500.4 H38

(R)-N-(5-(2-hydroxypropan-2- yl)-4′-((4-(2-hydroxypropoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide MS (ESI) m/e [M + 1]⁺ 516. H39

N-(5-(2-hydroxypropan-2-yl)-4′- ((6-(methylsulfonyl)-4- (tetrahydro-2H-pyran-4- yl)pyridin-2-yl)amino)-[2,3′- bipyridin]-6′-yl)acetamide MS (ESI) m/e [M + 1]⁺ 526. H40

N-(5-(2-hydroxypropan-2-yl)-4′- ((4-isobutoxy-6- (methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide MS (ESI) m/e [M + 1]⁺ 514. H41

(S)-N-(4′-((4-(sec-butoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2-hydroxypropan-2- yl)-[2,3′-bipyridin]-6′- yl)acetamide MS (ESI) m/e [M + 1]⁺ 514. H42

(R)-N-(4′-((4-(sec-butoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2-hydroxypropan-2- yl)-[2,3′-bipyridin]-6′- yl)acetamide MS (ESI) m/e [M + 1]⁺ 514.

Example J1: Synthesis of N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

Step 1: 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

A mixture of 3-bromo-1-methyl-1H-pyrazole (4.1 g, 25.5 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (9.7 g, 38.2 mmol), KOAc (10.0 g, 102.0 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (2.0 g, 2.5 mmol) in 1,4-dioxane (50 mL) was stirred at 95° C. under nitrogen atmosphere for 6 h. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with 20 mL of water. The resulting solution was extracted with EA (30 mL×3) and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE/EA=3:1 to 0:1) to give 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.6 g, 68%). MS (ESI) m/e [M+1]⁺ 127.

Step 2: tert-butyl (2-chloro-5-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)carbamate

A mixture of tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (3.5 g, 7.5 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.3 g, 11.0 mmol), K₃PO₄ (7.2 g, 3.3 mmol) and Pd(dppf)Cl₂ (805 mg, 1.1 mmol) in dioxane (50 mL) and H₂O (5 mL) was stirred at 100° C. for 12 h under nitrogen atmosphere. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with 20 mL of water. The resulting solution was extracted with EA (30 mL×3) and the combined organic layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE/EA=10:1 to 3:1) to give tert-butyl (2-chloro-5-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)carbamate (2.9 g, 82%). MS (ESI) m/e [M+1]⁺ 309.

Step 3: tert-butyl (2-acetamido-5-A1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)carbamate

A mixture of tert-butyl (2-chloro-5-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)carbamate (3.2 g, 10.3 mmol), acetamide (1.2 g, 20.7 mmol), Cs₂CO₃ (10.1 g, 31.0 mmol), Xant-phos (1.2 g, 2.1 mmol) and Pd₂(dba)₃ (916 mg, 1.0 mmol) in 1,4-dioxane (50 mL) was stirred at 110° C. for 12 h under nitrogen atmosphere. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with 20 mL of water. The resulting solution was extracted with EA (30 mL×3) and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE/EA=1:1 to 0:1) to give tert-butyl (2-acetamido-5-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)carbamate (1.3 g, 38%). ¹H NMR (400 MHz, CDCl₃) δ 10.70 (s, 1H), 9.13 (s, 1H), 8.41 (s, 1H), 8.08 (s, 1H), 7.43 (d, J=2.4 Hz, 1H), 6.59 (d, J=2.4 Hz, 1H), 3.98 (s, 3H), 2.21 (s, 3H), 1.57 (s, 9H). MS (ESI) m/e [M+1]⁺ 332.

Step 4: N-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide

A mixture of tert-butyl (2-acetamido-5-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)carbamate (1.3 g, 3.9 mmol) in TFA (5 mL) and DCM (5 mL) was stirred at 20° C. for 3 h. Upon completion of the reaction, the solvent was removed in vacuo and the residue was diluted with water, then sat. NaHCO₃ was added to adjust the pH value to 9. The resulting mixture was extracted with EA (30 mL×3) and the combined organic layers were dried over Na₂SO₄. The solvent was removed to give N-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide (810 mg, crude). MS (ESI) m/e [M+1]⁺ 232.

Step 5: N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

A mixture of N-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide (70 mg, 0.3 mmol), 2-bromo-4-methyl-6-(methylsulfonyl)pyridine (91 mg, 0.36 mmol), Pd₂dba₃ (28 mg, 0.03 mmol), BINAP (19 mg, 0.03 mmol) and Cs₂CO₃ (196 mg, 0.6 mmol) in dioxane (5 mL) was stirred at 125° C. under N₂ in a sealed tube for 6 h. The reaction mixture was filtered and the solid was washed with EA (10 mL). The filtration was concentrated and the residue was purified by Prep-TLC (DCM/MeOH=20:1) to give the N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide (35 mg, 29%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.47 (s, 1H), 10.43 (s, 1H), 9.27 (s, 1H), 8.64 (s, 1H), 7.90-7.85 (m, 1H), 7.45 (s, 1H), 7.18 (s, 1H), 6.95-6.90 (m, 1H), 4.04 (s, 3H), 3.48 (s, 3H), 2.44 (s, 3H), 2.11 (s, 3H). MS (ESI) m/e [M+1]⁺ 401.

Example J2: Synthesis of N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide

A mixture of N-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide (600 mg, 2.6 mmol), 2-bromo-4-isopropoxy-6-(methylsulfonyl)pyridine (916 mg, 3.1 mmol), Pd₂dba₃ (238 mg, 0.26 mmol), BINAP (162 mg, 0.26 mmol) and K₂CO₃ (718 mg, 5.2 mmol) in dioxane (20 mL) was stirred at 125° C. under N₂ in a sealed tube for 4 h. The reaction mixture was filtered and the solid was washed with EA (10 mL). The filtrate was concentrated and the residue was purified by column chromatography (DCM/MeOH=100:1-50:1) then combi-flash ((CH₃CN/H₂O, 0.1% HCOOH)=0-100%)) to give N-(4-((4-isopropoxy-6-(methyl sulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide (720 mg, 62%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H), 10.24 (s, 1H), 8.56 (s, 1H), 8.14 (s, 1H), 7.89-7.84 (m, 1H), 7.38 (s, 1H), 7.14 (s, 1H), 7.09 (s, 1H), 6.87-6.82 (m, 1H), 4.81-4.71 (m, 1H), 3.96 (s, 3H), 3.29 (s, 3H), 2.06 (s, 3H), 1.31 (d, J=5.9 Hz, 6H). MS (ESI) m/e [M+1]⁺ 444.

Example J3: Synthesis of N-(4-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide

A mixture of N-(4-amino-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide (300 mg, 1.3 mmol), 2-bromo-4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridine (477 mg, 1.56 mmol), Pd₂dba₃ (120 mg, 0.13 mmol), BINAP (80 mg, 0.13 mmol) and K₂CO₃ (360 mg, 2.6 mmol) in dioxane (20 mL) was stirred at 125° C. under N₂ in a sealed tube for 4 h. The reaction mixture was filtered and the solid was washed with EA (10 mL). The filtrate was concentrated and the residue was purified by column chromatography (DCM/MeOH=200:1-70:1) and the impure product was washed with CH₃CN (5 mL) to give N-(4-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridine-2-yl)amino)-5-(1-methyl-H-pyrazol-3-yl)pyridin-2-yl)acetamide (380 mg, 640). ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 10.30 (s, 1H), 8.55 (s, 1H), 8.10 (s, 1H), 7.86 (d, J=2.1 Hz, 1H), 7.39 (s, 1H), 7.20 (s, 10), 7.13 (s, 1H), 6.87 (d, J=2.1 Hz, 1H), 3.96-3.94 (N, 5H), 3.29 (s, 3H), 2.07 (s, 3H), 1.24-1.22 (s, 1H), 0.65-0.59 (m, 2H), 0.35-0.34 (in, 2H). MS (ESI) m/e [M+1]⁺ 456.

The following Examples were prepared in a similar manner to the product Example J1:

¹H NMR and LC/MS Example Compound Chemical Name m/z (M + 1) J4

N-(5-(1-methyl-1H- pyrazol-3-yl)-4-((6- sulfamoylpyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.61 (s, 1H), 10.66 (s, 1H), 9.75 (s, 1H), 8.67 (s, 1H), 8.05-7.88 (m, 2H), 7.47 (d, J = 6.4 Hz, 1H), 7.40-7.33 (m, 2H), 7.30 (d, J = 6.4 Hz, 1H), 6.97-6.92 (m, 1H), 4.04 (s, 3H), 2.16 (s, 3H). MS (ESI) m/e [M + 1]⁺ 388. J5

N-(4-((6- (ethylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.53 (s, 1H), 10.44 (s, 1H), 9.18 (s, 1H), 8.64 (s, 1H), 8.04-7.94 (m, 1H), 7.88-7.87 (m, 1H), 7.60-7.50 (m, 1H), 7.36 (d, J = 7.3 Hz, 1H), 6.95-6.91 (m, 1H), 4.00 (s, 3H), 3.73 (q, J = 7.3 Hz, 2H), 2.09 (s, 3H), 1.16 (t, J = 7.3 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 401. J6

N-(5-(1-methyl-1H- pyrazol-3-yl)-4-((3- (methylsulfonyl)phenyl) amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (s, 1H), 10.28 (s, 1H), 8.56 (s, 1H), 8.14 (s, 1H), 7.86-7.80 (m, 2H), 7.62-7.50 (m, 3H), 6.87 (s, 1H), 3.94 (s, 3H), 3.29 (s, 3H), 2.04 (s, 3H). MS (ESI) m/e [M + 1]⁺ 386. J7

N-(4-((3-cyano-5- (methylsulfonyl)phenyl) amino)-5-(1-methyl- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H), 10.36 (s, 1H), 8.59 (s, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 8.07 (s, 1H), 7.97-7.92 (m, 1H), 7.83 (d, J = 2.4 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 3.94 (s, 3H), 3.35 (s, 3H), 2.05 (s, 3H). MS (ESI) m/e [M + 1]⁺ 411. J8

N-(5-(1-methyl-1H- pyrazol-3-yl)-4-((3- methyl-5- (methylsulfonyl)phenyl) amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.38 (s, 1H), 10.22 (s, 1H), 8.55 (s, 1H), 8.13 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.63 (s, 1H), 7.44 (s, 2H), 6.86 (d, J = 2.4 Hz, 1H), 3.94 (s, 3H), 3.26 (s, 3H), 2.41 (s, 3H), 2.03 (s, 3H). MS (ESI) m/e [M + 1]⁺ 400. J9

N-(4-((3-methoxy-5- (methylsulfonyl)phenyl) amino)-5-(1-methyl- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 10.26 (s, 1H), 8.55 (s, 1H), 8.18 (s, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.38-7.32 (m, 1H), 7.25-7.21 (m, 1H), 7.15-7.10 (m, 1H), 6.86 (d, J = 2.4 Hz, 1H), 3.94 (s, 3H), 3.87 (s, 3H), 3.28 (s, 3H), 2.04 (s, 3H). MS (ESI) m/e [M + 1]⁺ 416. J10

N-(5-(1-methyl-1H- pyrazol-3-yl)-4-((3- (methylsulfonyl)-5- (trifluoromethoxy)phe- nyl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H), 10.34 (s, 1H), 8.60 (s, 1H), 8.21 (s, 1H), 7.86-7.85 (m, 2H), 7.66 (s, 1H), 7.48 (s, 1H), 6.86-6.85 (m, 1H), 3.96 (s, 3H), 3.38 (s, 3H), 2.07 (s, 3H). MS (ESI) m/e [M + 1]⁺ 470. J11

N-(5-(1-methyl-1H- pyrazol-3-yl)-4-((6- (methylsulfonyl)pyridin- 2-yl)amino)pyridin- 2-yl)actamide ¹H NMR (400 MHz, CDCl₃) δ 11.43 (s, 1H), 9.35 (s, 1H), 8.48 (s, 1H), 7.99 (s, 2H), 7.85-7.78 (m, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 4.04 (s, 3H), 3.51 (s, 3H), 2.22 (s, 3H). MS (ESI) m/e [M + 1]⁺ 387. J12

N-(4-((4-(2- methoxyethoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s, 1H), 10.43 (s, 1H), 9.18 (s, 1H), 8.63 (s, 1H), 7.89-7.84 (m, 1H), 7.14 (s, 1H), 6.95- 6.91 (m, 1H), 6.83 (s, 1H), 4.39-4.32 (m, 2H), 4.03 (s, 3H), 3.74-3.68 (m, 2H), 3.46 (s, 3H), 2.10 (s, 3H). MS (ESI) m/e [M + 1]⁺ 461. J13

N-(4-((4-(2- methoxypropoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.29 (s, 1H), 10.43 (s, 1H), 9.16 (s, 1H), 8.61 (s, 1H), 7.87-7.82 (m, 1H), 7.12 (s, 1H), 6.90- 6.85 (m, 1H), 6.82 (s, 1H), 4.24-4.15 (m, 2H), 4.00 (s, 3H), 3.73-3.66 (m, 1H), 3.44 (s, 3H), 2.08 (s, 3H), 1.19-1.15 (m, 3H). MS (ESI) m/e [M + 1]⁺ 475. J14

(R)-N-(4-((4-(2- methoxypropoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.31 (s, 1H), 10.45 (s, 1H), 9.17 (s, 1H), 8.63 (s, 1H), 7.90-7.82 (m, 1H), 7.15 (s, 1H), 6.96- 6.91 (m, 1H), 6.85 (s, 1H), 4.27-4.13 (m, 2H), 4.03 (s, 3H), 3.78-3.68 (m, 1H), 3.46 (s, 3H), 3.35 (s, 3H), 2.11 (s, 3H), 1.20 (d, J = 6.2 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 475. J15

N-(4-((4-(2- hydroxyethoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide 1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 10.44 (s, 1H), 9.19 (s, 1H), 8.63 (s, 1H), 7.90-7.86 (m, 1H), 7.14 (s, 1H), 6.95- 6.92 (m, 1H), 6.82 (s, 1H), 5.03-4.97 (m, 1H), 4.28-4.20 (m, 2H), 4.03 (s, 3H), 3.80- 3.72 (m, 2H), 3.46 (s, 3H), 2.10 (s, 3H). MS (ESI) m/e [M + 1]⁺ 447. J16

N-(4-((4-((trans)-3- hydroxycyclobutoxy)- 6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamde ¹H NMR (400 MHz, DMSO-d₆) δ 11.34 (s, 1H), 10.44 (s, 1H), 9.17 (s, 1H), 8.63 (s, 1H), 7.98-7.91 (m, 1H), 7.01 (s, 1H), 6.96- 6.91 (m, 1H), 6.63 (s, 1H), 5.32-5.26 (m, 1H), 5.12-5.04 (m, 1H), 4.45-4.35 (m, 1H), 4.02 (s, 3H), 3.46 (s, 3H), 2.46-2.30 (m, 4H), 2.10 (s, 3H). MS (ESI) m/e [M + 1]⁺ 473. J17

N-(4-((4-((cis)-3- hydroxycyclobutoxy)- 6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.34 (s, 1H), 10.43 (s, 1H), 9.15 (s, 1H), 8.62 (s, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.02 (s, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.67 (s, 1H), 5.29 (d, J = 6.8 Hz, 1H), 4.68-4.43 (m, 1H), 4.00 (s, 3H), 3.89-3.82 (m, 1H), 3.44 (s, 3H), 2.90-2.79 (m, 2H), 2.08 (s, 3H), 2.00- 1.92 (m, 2H). MS (ESI) m/e [M + 1]⁺ 473. J18

N-(4-((4-(3- methoxycyclobutoxy)- 6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s, 1H), 10.45 (s, 1H), 9.16 (s, 1H), 8.63 (s, 1H), 7.92-7.89 (m, 1H), 7.02 (s, 1H), 6.95- 6.91 (m, 1H), 6.65 (s, 1H), 5.13-5.05 (m, 1H), 4.15-4.07 (m, 1H), 4.02 (s, 3H), 3.46 (s, 3H), 3.18 (s, 3H), 2.48-2.34 (m, 4H), 2.10 (s, 3H). MS (ESI) m/e [M + 1]⁺ 487. J19

N-(4-((4- (methoxymethyl)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.52 (s, 1H), 10.46 (s, 1H), 9.28 (s, 1H), 8.66 (s, 1H), 7.95-7.90 (m, 1H), 7.52 (s, 1H), 7.23 (s, 1H), 6.98-6.94 (m, 1H), 4.59 (s, 2H), 4.03 (s, 3H), 3.50 (s, 3H), 3.40 (s, 3H), 2.11 (s, 3H). MS (ESI) m/e [M + 1]⁺ 431. J20

N-(4-((4- (cyanomethoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.51 (s, 1H), 10.46 (s, 1H), 9.21 (s, 1H), 8.66 (s, 1H), 7.90-7.85 (m, 1H), 7.27 (s, 1H), 6.95- 6.90 (m, 2H), 5.46 (s, 2H), 4.04 (s, 3H), 3.50 (s, 3H), 2.11 (s, 3H). MS (ESI) m/e [M + 1]⁺ 442. J21

N-(4-((4-methoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.35 (s, 1H), 10.45 (s, 1H), 9.18 (s, 1H), 8.64 (s, 1H), 7.93-7.89 (m, 1H), 7.14 (s, 1H), 6.96- 6.92 (m, 1H), 6.83 (s, 1H), 4.03 (s, 3H), 3.97 (s, 3H), 3.46 (s, 3H), 2.11 (s, 3H). MS (ESI) m/e [M + 1]⁺ 417. J22

N-(5-(1-methyl-1H- pyrazol-3-yl)-4-((6- (methylsulfonyl)-4- (oxetan-3- yloxy)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.38 (s, 1H), 10.46 (s, 1H), 9.17 (s, 1H), 8.64 (s, 1H), 7.93-7.89 (m, 1H), 7.03 (s, 1H), 6.95- 6.90 (m, 1H), 6.59 (s, 1H), 5.62-5.54 (m, 1H), 5.05-4.94 (m, 2H), 4.67-4.60 (m, 2H), 4.03 (s, 3H), 3.47 (s, 3H), 2.11 (s, 3H). MS (ESI) m/e [M + 1]⁺ 459. J23

N-(4-((3-methoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (s, 1H), 10.41 (s, 1H), 9.49 (s, 1H), 8.64 (s, 1H), 7.89-7.86 (m, 1H), 7.60-7.56 (m, 1H), 7.54-7.50 (m, 1H), 6.92-6.89 (m, 1H), 4.08 (s, 3H), 3.99 (s, 3H), 3.45 (s, 3H), 2.09 (s, 3H). MS (ESI) m/e [M + 1]⁺ 417. J24

N-(4-((4-(2- hydroxypropoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.30 (s, 1H), 10.44 (s, 1H), 9.18 (s, 1H), 8.63 (s, 1H), 7.94-7.89 (m, 1H), 7.14 (s, 1H), 6.95- 6.91 (m, 1H), 6.82 (s, 1H), 5.04-4.98 (m, 1H), 4.12-3.96 (m, 5H), 3.46 (s, 3H), 2.11 (s, 3H), 1.22-1.12 (m, 2H). MS (ESI) m/e [M + 1]⁺ 461. J25

N-(5-(1-methyl-1H- pyrazol-3-yl)-4-((6- (methylsulfonyl)-4- (oxetan-3- ylmethoxy)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.30 (s, 1H), 10.43 (s, 1H), 9.17 (s, 1H), 8.62 (s, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.15 (s, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.83 (s, 1H), 4.72- 4.69 (m, 2H), 4.45-4.42 (m, 4H), 4.01 (s, 3H), 3.49-3.42 (m, 4H), 2.08 (s, 3H). MS (ESI) m/e [M + 1]⁺ 473. J26

N-(4-((4-cyano-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (s, 1H), 10.53 (s, 1H), 9.28 (s, 1H), 8.70 (s, 1H), 7.96 (s, 1H), 7.95-7.90 (m, 1H), 7.84 (s, 1H), 6.99-6.95 (m, 1H), 4.07 (s, 3H), 3.54 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M + 1]⁺ 412. J27

N-(5-(1-methyl-1H- pyrazol-3-yl)-4-((3- methyl-6- (methylsulfonyl)pyridin- 2-yl)amino)pyridin- 2-yl)acetamide ¹H NMR (400 MHz, DMOS-d₆) δ 11.29 (s, 1H), 10.45 (s, 1H), 9.40 (s, 1H), 8.71 (s, 1H), 7.92-7.89 (m, 2H), 7.54 (d, J = 7.5 Hz, 1H), 6.98-6.97 (m, 1H), 3.98 (s, 3H), 3.47 (s, 3H), 2.56 (s, 3H), 2.11 (s, 3H). MS (ESI) m/e [M + 1]⁺ 401. J28

N-(4-((6- (cyclopropylsulfonyl)py- ridin-2-yl)amino)-5- (1-methyl-1H-pyrazol- 3-yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.50 (s, 1H), 10.44 (s, 1H), 9.18 (s, 1H), 8.66 (s, 1H), 8.05-7.95 (m, 1H), 7.90-7.89 (m, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 6.95-6.90 (m, 1H), 4.02 (s, 3H), 3.70-3.65 (m, 1H), 2.09 (s, 3H), 1.15- 1.05 (m, 4H). MS (ESI) m/e [M + 1]⁺ 413. J29

N-(4-((6- (isopropylsulfonyl)pyri- din-2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.52 (s, 1H), 10.44 (s, 1H), 9.17 (s, 1H), 8.66 (s, 1H), 8.01 (t, J = 7.6 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 6.94 (d, J = 2.1 Hz, 1H), 4.51-4.35 (m, 1H), 4.02 (s, 3H), 2.11 (s, 3H), 1.22 (d, J = 6.2 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 415. J30

N-(4-((3-fluoro-5- (methylsulfonyl)phenyl) amino)-5-(1-methyl- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 1H), 10.35 (s, 1H), 8.60 (s, 1H), 8.21 (s, 1H), 7.86 (s, 1H), 7.69 (s, 1H), 7.55 (d, J = 4.6 Hz, 1H), 7.40 (s, 1H), 6.87 (d, J = 4.6 Hz, 1H), 3.96 (s, 3H), 3.34 (s, 3H), 2.07 (s, 3H). MS (ESI) m/e [M + 1]⁺ 404. J31

N-(4-((3-chloro-5- (methylsulfonyl)phenyl) amino)-5-(1-methyl- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 1H), 10.30 (s, 1H), 8.59 (s, 1H), 8.17 (s, 1H), 7.85-7.84 (m, 1H), 7.79 (s, 1H), 7.73 (s, 1H), 7.59 (s, 1H), 6.88-6.85 (m, 1H), 3.96 (s, 3H), 3.35 (s, 3H), 2.07 (s, 3H). MS (ESI) m/e [M + 1]⁺ 420. J32

N-(4-((3- (difluoromethyl)-5- (methylsulfonyl)phenyl) amino)-5-(1-methyl- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 10.34 (s, 1H), 8.60 (s, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.86-7.83 (m, 1H), 7.76 (s, 1H), 7.17 (s, 1H), 6.88-6.82 (m, 1H), 3.96 (s, 3H), 3.36 (s, 3H), 2.06 (s, 3H). MS (ESI) m/e [M + 1]⁺ 436. J33

N-(5-(1-methyl-1H- pyrazol-3-yl)-4-((3- (methylsulfonyl)-5- (trifluoromethyl)phenyl) amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 10.34 (s, 1H), 8.60 (s, 1H), 8.20 (s, 1H), 8.10 (s, 1H), 7.99 (s, 1H), 7.87-7.84 (m, 1H), 7.82 (s, 1H), 6.89-6.85 (m, 1H), 3.96 (s, 3H), 3.40 (s, 3H), 2.07 (s, 3H). MS (ESI) m/e [M + 1]⁺ 454. J34

N-(4-((3- (methoxymethyl)-5- (methylsulfonyl)phenyl) amino)-5-(1-methyl- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 10.28 (s, 1H), 8.57 (s, 1H), 8.13 (s, 1H), 7.89-7.85 (m, 1H), 7.77 (s, 1H), 7.58 (s, 1H), 7.55 (s, 1H), 6.89-6.87 (m, 1H), 4.54 (s, 2H), 3.96 (s, 3H), 3.36 (s, 3H), 3.30 (s, 3H), 2.06 (s, 3H). MS (ESI) m/e [M + 1]⁺ 430. J35

N-(4-((3-(2- methoxyethoxy)-5- (methylsulfonyl)phenyl) amino)-5-(1-methyl- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 10.27 (s, 1H), 8.57 (s, 1H), 8.17 (s, 1H), 7.88-7.85 (m, 1H), 7.41 (s, 1H), 7.22 (s, 1H), 7.14 (s, 1H), 6.88-6.84 (m, 1H), 4.27-4.21 (m, 2H), 3.96 (s, 3H), 3.72- 3.66 (m, 2H), 3.29 (s, 3H), 2.06 (s, 3H). MS (ESI) m/e [M + 1]⁺ 460. J36

N-(4-((3- cyclopropoxy-5- (methylsulfonyl)phenyl) amino)-5-(1-methyl- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 10.29 (s, 1H), 8.57 (s, 1H), 8.19 (s, 1H), 7.90-7.80 (m, 1H), 7.44 (s, 1H), 7.32 (s, 1H), 7.24 (s, 1H), 6.90-6.80 (m, 1H), 4.05-4.00 (m, 1H), 3.96 (s, 3H), 3.30 (s, 3H), 2.06 (s, 3H), 0.82-0.80 (m, 2H), 0.73- 0.71 (m, 2H). MS (ESI) m/e [M + 1]⁺ 442. J37

N-(4-((3-((trans)-3- hydroxycyclobutoxy)- 5- (methylsulfonyl)phenyl) amino)-5-(1-methyl- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H), 10.23 (s, 1H), 8.57 (s, 1H), 8.17 (s, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.41 (s, 1H), 7.03 (s, 1H), 6.99 (s, 1H), 6.87 (d, J = 2.1 Hz, 1H), 5.25 (s, 1H), 4.99-4.96 (m, 1H), 4.40-4.35 (m, 1H), 3.96 (s, 3H), 3.29 (s, 3H), 2.40-2.30 (m, 4H), 2.06 (s, 3H). MS (ESI) m/e [M + 1]⁺ 472. J38

N-(5-(1-methyl-1H- pyrazol-3-yl)-4-((6- (methylsulfonyl)-4- phenylpyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.54 (s, 1H), 10.47 (s, 1H), 9.28 (s, 1H), 8.67 (s, 1H), 7.94-7.88 (m, 3H), 7.79 (s, 1H), 7.66- 7.52 (m, 4H), 6.95-6.94 (m, 1H), 4.04 (s, 3H), 3.53 (s, 3H), 2.13 (s, 3H). MS (ESI) m/e [M + 1]⁺ 463. J39

N-(5-(1-methyl-1H- pyrazol-3-yl)-4-((6- (methylsulfonyl)-4- phenoxypyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.43 (s, 1H), 10.46 (s, 1H), 9.21 (s, 1H), 8.64 (s, 1H), 7.88-7.87 (m, 1H), 7.60-7.50 (m, 2H), 7.40-7.30 (m, 1H), 7.35-7.30 (m, 2H), 6.96-6.90 (m, 1H), 6.92 (s, 1H), 6.81 (s, 1H), 3.93 (s, 3H), 3.48 (s, 3H), 2.11 (s, 3H). MS (ESI) m/e [M + 1]⁺ 479. J40

N-(4-((4-chloro-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.53 (s, 1H), 10.49 (s, 1H), 9.23 (s, 1H), 8.67 (s, 1H), 7.92-7.89 (m, 1H), 7.55 (s, 2H), 6.95- 6.92 (m, 1H), 4.04 (s, 3H), 3.52 (s, 3H), 2.11 (s, 3H). MS (ESI) m/e [M + 1]⁺ 421. J41

N-(4-((4-(1- methoxyethyl)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.49 (s, 1H), 10.46 (s, 1H), 9.26 (s, 1H), 8.66 (s, 1H), 7.95-7.90 (m, 1H), 7.51 (s, 1H), 7.24 (s, 1H), 6.96-6.93 (m, 1H), 4.59-4.45 (m, 1H), 4.04 (s, 3H), 3.50 (s, 3H), 3.25 (s, 3H), 2.11 (s, 3H), 1.39 (d, J = 6.4 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 445. J42

N-(4-((4- (difluoromethyl)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 10.50 (s, 1H), 9.29 (s, 1H), 8.68 (s, 1H), 7.95-7.90 (m, 1H), 7.64 (s, 1H), 7.52 (s, 1H), 7.25-7.15 (m, 1H), 6.94-6.91 (m, 1H), 4.04 (s, 3H), 3.54 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M + 1]⁺ 437. J43

N-(4-((4-ethoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.31 (s, 1H), 10.42 (s, 1H), 9.17 (s, 1H), 8.63 (s, 1H), 7.89 (s, 1H), 7.11 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.79 (s, 1H), 4.27 (d, J = 7.0 Hz, 2H), 4.02 (s, 3H), 3.46 (s, 3H), 2.10 (s, 3H), 1.38 (t, J = 6.9 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 431. J44

N-(4-((4-cyclobutoxy- 6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.34 (s, 1H), 10.43 (s, 1H), 9.17 (s, 1H), 8.63 (s, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.03 (s, 1H), 6.92 (d, J = 2.4 Hz, 1H), 6.68 (s, 1H), 5.00- 4.96 (m, 1H), 4.02 (s, 3H), 3.46 (s, 3H), 2.16-2.10 (m, 5H), 1.85-1.83 (m, 1H), 1.74-1.69 (m, 1H). MS (ESI) m/e [M + 1]⁺ 457. J45

N-(4-((4- (cyclopentyloxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.32 (s, 1H), 10.43 (s, 1H), 9.17 (s, 1H), 8.63 (s, 1H), 7.89-7.85 (m, 1H), 7.07 (s, 1H), 6.95- 6.91 (m, 1H), 6.75 (s, 1H), 5.13-5.07 (m, 1H), 4.02 (s, 3H), 3.46 (s, 3H), 2.10 (s, 3H), 2.05-1.93 (m, 2H), 1.87-1.52 (m, 6H). MS (ESI) m/e [M + 1]⁺ 471. J46

N-(5-(1-methyl-1H- pyrazol-3-yl)-4-((6- (methylsulfonyl)-4- ((tetrahydrofuran-3- yl)oxy)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.35 (s, 1H), 10.44 (s, 1H), 9.17 (s, 1H), 8.64 (s, 1H), 7.89-7.85 (m, 1H), 7.10 (s, 1H), 6.96- 6.91 (m, 1H), 6.79 (s, 1H), 5.36-5.31 (m, 1H), 4.02 (s, 3H), 3.94-3.83 (m, 3H), 3.82- 3.74 (m, 1H), 3.46 (s, 3H), 2.36-2.25 (m, 1H), 2.10 (s, 3H), 2.08-2.00 (m, 1H). MS (ESI) m/e [M + 1]⁺ 473. J47

(R)-N-(4-((4-(2- hydroxypropoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.29 (s, 1H), 10.44 (s, 1H), 9.17 (s, 1H), 8.63 (s, 1H), 7.90-7.85 (m, 1H), 7.14 (s, 1H), 6.95- 6.91 (m, 1H), 6.82 (s, 1H), 5.04-4.95 (m, 1H), 4.12-3.92 (m, 5H), 3.46 (s, 3H), 2.11 (s, 3H), 1.17 (d, J = 5.9 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 461. J48

N-(4-((4-(2,3- dihydroxypropoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.32 (s, 1H), 10.44 (s, 1H), 9.19 (s, 1H), 8.63 (s, 1H), 7.89-7.86 (m, 1H), 7.15 (s, 1H), 6.95- 6.91 (m, 1H), 6.83 (s, 1H), 5.16-4.97 (m, 1H), 4.84-4.64 (m, 1H), 4.30-4.22 (m, 1H), 4.12-4.02 (m, 1H), 4.02 (s, 3H), 3.87- 3.80 (m, 1H), 3.49-3.43 (m, 5H), 2.11 (s, 3H). MS (ESI) m/e [M + 1]⁺ 477. J49

N-(4-((3-isopropoxy- 6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H), 10.38 (s, 1H), 9.25 (s, 1H), 8.58 (s, 1H), 7.86-7.83 (m, 1H), 7.54-7.50 (m, 2H), 6.89-6.85 (m, 1H), 4.94-4.86 (m, 1H), 3.96 (s, 3H), 3.36 (s, 3H), 2.05 (s, 3H), 1.40 (d, J = 6.0 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 445. J50

N-(4-((5-methoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.03 (s, 1H), 10.41 (s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 7.90 (d, J = 2.8 Hz, 1H), 7.80 (d, J = 6.4 Hz, 1H), 7.48-7.45 (d, J = 6.4 Hz, 1H), 6.90 (d, J = 2.8 Hz, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 3.39 (s, 3H), 2.08 (s, 3H). MS (ESI) m/e [M + 1]⁺ 417. J51

N-(5-(1-methyl-1H- pyrazol-3-yl)-4-((5- methyl-6- (methylsulfonyl)pyridin- 2-yl)amino)pyridin- 2-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.24 (s, 1H), 10.42 (s, 1H), 8.91 (s, 1H), 8.63 (s, 1H), 7.88 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 2.1 Hz, 1H), 4.00 (s, 3H), 3.47 (s, 3H), 2.53 (s, 3H), 2.09 (s, 3H). MS (ESI) m/e [M + 1]⁺ 401. J52

N-(5-(1-methyl-1H- pyrazol-3-yl)-4-((6- (methylsulfonyl)-4- (trifluoromethyl)pyridin- 2-yl)amino)pyridin- 2-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.61 (s, 1H), 10.52 (s, 1H), 9.24 (s, 1H), 8.68 (s, 1H), 7.90-7.85 (m, 1H), 7.73 (s, 1H), 7.67 (s, 1H), 6.95-6.91 (m, 1H), 4.03 (s, 3H), 3.55 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M + 1]⁺ 455. J53

N-(4-((6- (ethylsulfonyl)-4- isopropoxypyridin-2- yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.19 (s, 1H), 10.36 (s, 1H), 9.03 (s, 1H), 8.58 (s, 1H), 7.86-7.83 (m, 1H), 7.05 (s, 1H), 6.88- 6.85 (m, 1H), 6.74 (s, 1H), 4.95-4.82 (m, 1H), 3.97 (s, 3H), 3.68-3.62 (m, 2H), 2.06 (s, 3H), 1.30 (d, J = 5.9 Hz, 6H), 1.13 (t, J = 7.3 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 459. J54

N-(4-((5-fluoro-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.34 (s, 1H), 10.39 (s, 1H), 8.94 (s, 1H), 8.60 (s, 1H), 7.95 (d, J = 9.4 Hz, 1H), 7.84-7.81 (m, 1H), 7.43 (d, J = 9.4 Hz, 1H), 6.87- 6.82 (m, 1H), 3.96 (s, 3H), 3.49 (s, 3H), 2.05 (s, 3H). MS (ESI) m/e [M + 1]⁺ 405. J55

(S)-N-(4-((3-(2- hydroxypropoxy)-5- (methylsulfonyl)phenyl) amino)-5-(1-methyl- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H), 10.23 (s, 1H), 8.57 (s, 1H), 8.19 (s, 1H), 7.85-7.81 (m, 1H), 7.40 (s, 1H), 7.20 (s, 1H), 7.13 (s, 1H), 6.87-6.81 (m, 1H), 4.92 (s, 1H), 4.02-3.92 (m, 6H), 3.29 (s, 3H), 2.06 (s, 3H), 1.16 (d, J = 5.7 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 460. J56

N-(4-((3-(2- hydroxyethoxy)-5- (methylsulfonyl)phenyl) amino)-5-(1-methyl- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H), 10.25 (s, 1H), 8.57 (s, 1H), 8.18 (s, 1H), 7.85-7.80 (m, 1H), 7.40 (s, 1H), 7.20 (s, 1H), 7.13 (s, 1H), 6.87-6.82 (m, 1H), 4.92 (s, 1H), 4.17-4.09 (m, 2H), 3.96 (s, 3H), 3.78-3.71 (m, 2H), 3.29 (s, 3H), 2.06 (s, 3H). MS (ESI) m/e [M + 1]⁺ 446. J57

(R)-N-(4-((3-(2- hydroxypropoxy)-5- (methylsulfonyl)phenyl) amino)-5-(1-methyl- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H), 10.23 (s, 1H), 8.57 (s, 1H), 8.19 (s, 1H), 7.85-7.80 (m, 1H), 7.40 (s, 1H), 7.20 (s, 1H), 7.13 (s, 1H), 6.87-6.82 (m, 1H), 4.92 (s, 1H), 4.02-3.92 (m, 6H), 3.29 (s, 3H), 2.06 (s, 3H), 1.16 (d, J = 5.7 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 460. J58

N-(4-((4- (difluoromethoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.51 (s, 1H), 10.47 (s, 1H), 9.22 (s, 1H), 8.66 (s, 1H), 7.90 (d, J = 2.8 Hz, 1H), 7.70-7.65 (m, 1H), 7.35 (s, 1H), 7.10 (s, 1H), 6.93 (d, J = 2.8 Hz, 1H), 4.03 (s, 3H), 3.52 (s, 3H), 2.11 (s, 3H). MS (ESI) m/e [M + 1]⁺ 453. J59

N-(4-((4-isobutoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.26 (s, 1H), 10.42 (s, 1H), 9.16 (s, 1H), 8.62 (s, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.12 (s, 1H), 6.91 (d, J = 2.2 Hz, 1H), 6.82 (s, 1H), 4.03 (s, 3H), 4.05-4.00 (m, 2H), 3.45 (s, 3H), 2.10 (s, 3H), 2.09-2.03 (m, 1H), 1.01 (d, J = 6.7 Hz, 6H). MS (ESI) m/z [M + 1]⁺ 459. J60

(S)-N-(4-((4-(sec- butoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.28 (s, 1H), 10.63-10.60 (m, 0H), 10.42 (s, 1H), 9.16 (s, 1H), 8.62 (s, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.09-7.05 (m, 1H), 6.91 (d, J = 2.3 Hz, 1H), 6.78 (s, 1H), 4.75-4.67 (m, 1H), 4.02 (s, 3H), 3.46 (s, 3H), 2.10 (s, 3H), 1.78-1.61 (m, 2H), 1.31 (d, J = 6.0 Hz, 3H), 0.95 (t, J = 7.5 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 459. J61

N-(5-(1-methyl-1H- pyrazol-3-yl)-4-((6- (methylsulfonyl)-4- (tetrahydro-2H-pyran- 4-yl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.44 (s, 1H), 10.43 (s, 1H), 9.24 (s, 1H), 8.64 (s, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.48 (s, 1H), 7.18 (s, 1H), 6.93 (d, J = 2.3 Hz, 1H), 4.05 (s, 3H), 3.99-3.96 (m, 2H), 3.50-3.41 (m, 5H), 3.08-2.93 (m, 1H), 2.11 (s, 3H), 1.81- 1.71 (m, 4H). MS (ESI) m/e [M + 1]⁺ 471. J62

N-(4-((3- (difluoromethoxy)-5- (methylsulfonyl)phenyl) amino)-5-(1-methyl- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (s, 1H), 10.31 (s, 1H), 8.59 (s, 1H), 8.20 (s, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.71 (s, 1H), 7.46 (s, 1H), 7.45-7.42 (m, 1H), 7.34 (s, 1H), 6.87 (d, J = 2.2 Hz, 1H), 3.96 (s, 3H), 3.34 (s, 3H), 2.07 (s, 3H). MS (ESI) m/e [M + 1]⁺ 452. J63

N-(4-((3- (difluoromethoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.79 (s, 1H), 10.48 (s, 1H), 9.45 (s, 1H), 8.70 (s, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.59- 7.56 (m, 1H), 6.96 (d, J = 2.1 Hz, 1H), 3.97 (s, 3H), 3.51 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M + 1]⁺ 453. J64

N-(5-(1-methyl-1H- pyrazol-3-yl)-4-((7- (methylsulfonyl)-2,3- dihydro- [1,4]dioxino[2,3- c]pyridin-5- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 10.41 (s, 1H), 9.45 (s, 1H), 8.65 (s, 1H), 7.89-7.85 (m, 1H), 7.16 (s, 1H), 6.95- 6.90 (m, 1H), 4.63-4.59 (m, 2H), 4.53- 4.48 (m, 2H), 3.99 (s, 3H), 3.47 (s, 3H), 2.11 (s, 3H). MS (ESI) m/e [M + 1]⁺ 445. J65

(R)-N-(4-((4-(sec- butoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.28 (s, 1H), 10.42 (s, 1H), 9.17 (s, 1H), 8.63 (s, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.09-7.05 (m, 1H), 6.92 (d, J = 2.2 Hz, 1H), 6.78 (s, 1H), 4.74-4.66 (m, 1H), 4.02 (s, 3H), 3.46 (s, 3H), 2.10 (s, 3H), 1.77-1.60 (m, 2H), 1.31 (d, J = 6.0 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 459.

Example M1: Synthesis of N-(5-(1-cyclopropyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

Step 1: 3-bromo-1-cyclopropyl-1H-pyrazole

A mixture of Copper (II) acetate anhydrous (8.2 g, 41 mmol) and 2,2′bipyridyl (6.4 g, 41 mmol) in DCE (80 mL) was warmed to 50° C. and stirred for 10 min before adding to a mixture of 3-bromo-1H-pyrazole (6 g, 41 mmol), cyclopropylboronic acid (3.5 g, 41 mmol) and Na₂CO₃ (9.6 g, 90 mmol) in DCE (120 mL). The reaction mixture was stirred at 70° C. under O₂ atmosphere (O₂ balloon) for 2 d. The solvent was removed and the residue was dissolved in EA (300 mL) and washed with NH₄Cl solution (300 mL×2) and brine (50 mL). The organic layer was dried over with Na₂SO₄ and filtered. The filtrate was concentrated and the residue was purified by column chromatography (PE/EA=10: 1-5:1) to give 3-bromo-1-cyclopropyl-1H-pyrazole (5.5 g, impure). MS (ESI) m/e [M+1]⁺ 187.

Step 2: tert-butyl (2-chloro-5-(1-cyclopropyl-1H-pyrazol-3-yl)pyridin-4-yl)carbamate

A mixture of 3-bromo-1-cyclopropyl-1H-pyrazole (5 g, 26.7 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.34 g, 12 mmol), Pd(PPh₃)₂Cl₂ (702 mg, 1 mmol) and KOAc (5.2 g, 53.4 mmol) in dioxane (100 mL) was stirred at 120° C. under N₂ for 6 hrs. The reaction mixture was cooled to 90° C. and tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (4.9 g, 16 mmol), K₂CO₃ (7.37 g, 53.4 mmol) and H₂O (20 mL) and the mixture was stirred at 100° C. for 2 h. The reaction mixture was cooled and diluted with EA (200 mL) and washed with H₂O (200 mL) and brine (200 mL). The organic layer was dried over with Na₂SO₄ and filtered. The filtrate was concentrated and the residue was purified by column chromatography (PE/EA=10: 1-2:1) to give tert-butyl (2-chloro-5-(1-cyclopropyl-1H-pyrazol-3-yl)pyridin-4-yl)carbamate (4.5 g, 84%). MS (ESI) m/e [M+1]⁺ 335.

Step 3: tert-butyl (2-acetamido-5-(1-cyclopropyl-1H-pyrazol-3-yl)pyridin-4-yl)carbamate

A mixture of tert-butyl (2-chloro-5-(1-cyclopropyl-1H-pyrazol-3-yl)pyridin-4-yl)carbamate (500 mg, 1.5 mmol), acetamide (177 mg, 3 mmol), Pd₂dba₃ (137 mg, 0.15 mmol), Xant-Phos (87 mg, 0.15 mmol) and Cs₂CO₃ (978 mg, 3 mmol) in dioxane (20 mL) was stirred at 130° C. under N₂ in a sealed tube for 4 hs. The reaction mixture was filtered and the solid was washed with EA (10 mL). The filtrate was concentrated and the residue was purified by column chromatography (DCM/MeOH=70:1 to 40:1) to give tert-butyl (2-acetamido-5-(1-cyclopropyl-1H-pyrazol-3-yl)pyridin-4-yl)carbamate (400 mg, 75%). MS (ESI) m/e [M+1]⁺ 358.

Step 4: N-(4-amino-5-(1-cyclopropyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide

A solution of tert-butyl (2-acetamido-5-(1-cyclopropyl-1H-pyrazol-3-yl)pyridin-4-yl)carbamate (400 mg, 1.12 mmol) in TFA/DCM (14 mL, 1:3) was stirred at rt for 4 hs. The solvent evaporated and the residue was diluted with EA (20 mL) and washed with NaHCO₃ solution (10 mL) and brine (10 mL). The organic layer was dried over with Na₂SO₄ and filtered. The filtrate was concentrated to give the crude product N-(4-amino-5-(1-cyclopropyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide (300 mg). MS (ESI) m/e [M+1]⁺ 258.

Step 5: N-(5-(1-cyclopropyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

A mixture of N-(4-amino-5-(1-cyclopropyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide (60 mg, 0.23 mmol), 2-bromo-6-(methylsulfonyl)pyridine (66 mg, 0.28 mmol), Pd₂dba₃ (18 mg, 0.02 mmol), BINAP (12 mg, 0.02 mmol) and K₂CO₃ (60 mg, 0.46 mmol) in dioxane (5 mL) was stirred at 130° C. under N₂ in a sealed tube for 4 h. The reaction mixture was filtered and the solid was washed with EA (10 mL). The filtrate was concentrated and the residue was purified by prep-TLC (DCM:MeOH=20:1) twice to give N-(5-(1-cyclopropyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide (43 mg, 45%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.47 (s, 1H), 10.46 (s, 1H), 9.23 (s, 1H), 8.64 (s, 1H), 8.05-8.00 (m, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 6.93 (d, J=2.4 Hz, 1H), 3.96-3.86 (m, 1H), 3.48 (s, 3H), 2.09 (s, 3H), 1.20-1.16 (m, 2H), 1.08-1.04 (m, 2H). MS (ESI) m/e [M+1]⁺ 413.

The following Examples were prepared in a similar manner to the product Example M1:

¹H NMR and LC/MS Example Compound Chemical Name m/z (M + 1) M2

N-(5-(1-cyclopropyl- 1H-pyrazol-3-yl)-4-((4- isopropoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 10.46 (s, 1H), 9.14 (s, 1H), 8.64 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.06 (s, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.67 (s, 1H), 4.88-4.82 (m, 1H), 3.96-3.92 (m, 1H), 3.46 (s, 3H), 2.11 (s, 3H), 1.36 (d, J = 5.2 Hz, 6H), 1.25-1.21 (m, 2H), 1.07- 1.05 (m, 2H). MS (ESI) m/e [M + H]⁺ 471. M3

N-(5-(1-cyclopropyl- 1H-pyrazol-3-yl)-4-((4- methyl-6- (methylsulfonyl)pyridin- 2-yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.40 (s, 1H), 10.46 (s, 1H), 9.22 (s, 1H), 8.65 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.47 (s, 1H), 7.05 (s, 1H), 6.95 (d, J = 2.4 Hz, 1H), 3.95-3.92 (m, 1H), 3.47 (s, 3H), 2.45 (s, 3H), 2.11 (s, 3H), 1.20-1.15 (m, 2H), 1.09-1.05 (m, 2H). MS (ESI) m/e [M + 1]⁺ 427. M4

N-(5-(1-cyclopropyl- 1H-pyrazol-3-yl)-4-((4- (2-methoxyethoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s, 1H), 10.47 (s, 1H), 9.12 (s, 1H), 8.64 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.14 (s, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.73 (s, 1H), 4.35-4.33 (m, 2H), 3.93-3.90 (m, 1H), 3.75-3.71 (m, 2H), 3.46 (s, 3H), 3.34 (s, 3H), 2.11 (s, 3H), 1.25-1.20 (m, 2H), 1.07-1.02 (m, 2H). MS (ESI) m/e [M + 1]⁺ 487. M5

N-(5-(1-ethyl-1H- pyrazol-3-yl)-4-((6- (methylsulfonyl)pyridin- 2-yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.61 (s, 1H), 10.45 (s, 1H), 9.26 (s, 1H), 8.70- 8.60 (m, 1H), 8.10-8.00 (m, 1H), 7.94 (s, 1H), 7.58-7.49 (m, 1H), 7.35-7.25 (m, 1H), 7.00-6.90 (m, 1H), 4.31 (q, J = 7.3 Hz, 2H), 3.48 (s, 3H), 2.09 (s, 3H), 1.48 (t, J = 7.3 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 401. M6

N-(5-(1-ethyl-1H- pyrazol-3-yl)-4-((4- isopropoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.41 (s, 1H), 10.44 (s, 1H), 9.16 (s, 1H), 8.64 (s, 1H), 8.00-7.90 (m, 1H), 7.10-6.95 (m, 1H), 6.93 (s, 1H), 6.73 (s, 1H), 4.95- 4.87 (m, 1H), 4.35-4.27 (m, 2H), 3.46 (s, 3H), 2.11 (s, 3H), 1.50 (t, J = 7.2 Hz, 3H), 1.35 (d, J = 5.9 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 459. M7

N-(5-(1-ethyl-1H- pyrazol-3-yl)-4-((4- (methoxymethyl)-6- (methylsulfonyl)pyridin- 2-yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.62 (s, 1H), 10.46 (s, 1H), 9.28 (s, 1H), 8.67 (s, 1H), 8.05-7.95 (m, 1H), 7.51 (s, 1H), 7.18 (s, 1H), 7.05-6.95 (m, 1H), 4.59 (s, 2H), 4.36-4.28 (m, 2H), 3.50 (s, 3H), 3.40 (s, 3H), 2.11 (s, 3H), 1.51 (t, J = 7.3 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 445. M8

N-(5-(1-ethyl-1H- pyrazol-3-yl)-4-((3- (methylsulfonyl)phenyl) amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (s, 1H), 10.40 (s, 1H), 8.58 (s, 1H), 8.19 (s, 1H), 7.98-7.87 (m, 1H), 7.84 (s, 1H), 7.72-7.58 (m, 3H), 6.95-6.85 (m, 1H), 4.29-4.21 (m, 2H), 3.30 (s, 3H), 2.06 (s, 3H), 1.45 (t, J = 7.3 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 400. M9

N-(5-(1-ethyl-1H- pyrazol-3-yl)-4-((3- methoxy-5- (methylsulfonyl)phenyl) amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (s, 1H), 10.39 (s, 1H), 8.58 (s, 1H), 8.23 (s, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.39 (s, 1H), 7.22 (s, 1H), 7.12 (s, 1H), 6.88 (d, J = 2.1 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 3.89 (s, 3H), 3.29 (s, 3H), 2.07 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 430. M10

N-(4-((3-cyano-5- (methylsulfonyl)phenyl) amino)-5-(1-ethyl-1H- pyrazol-3-yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1H), 10.44 (s, 1H), 9.12 (s, 1H), 8.62 (s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.97 (d, J = 2.2 Hz, 1H), 7.90 (s, 1H), 6.87 (d, J = 2.2 Hz, 1H), 4.26 (q, J = 7.3 Hz, 2H), 3.37 (s, 3H), 2.08 (s, 3H), 1.44 (t, J = 7.3 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 425. M11

N-(5-(1-ethyl-1H- pyrazol-3-yl)-4-((3- methyl-5- (methylsulfonyl)phenyl) amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.38 (s, 1H), 10.33 (s, 1H), 8.57 (s, 1H), 8.17 (s, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.64 (s, 1H), 7.45 (s, 2H), 6.88 (d, J = 2.1 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 3.28 (s, 3H), 2.43 (s, 3H), 2.06 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 414. M12

N-(5-(1-ethyl-1H- pyrazol-3-yl)-4-((3- (methoxymethyl)-5- (methylsulfonyl)phenyl) amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H), 10.37 (s, 1H), 8.58 (s, 1H), 8.17 (s, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.77 (s, 1H), 7.56 (s, 1H), 7.53 (s, 1H), 6.88 (d, J = 2.2 Hz, 1H), 4.54 (s, 2H), 4.25 (q, J = 7.3 Hz, 2H), 3.36 (s, 3H), 3.30 (s, 3H), 2.06 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 444. M13

N-(5-(1-ethyl-1H- pyrazol-3-yl)-4-((3- (methylsulfonyl)-5- (trifluoromethyl)phenyl) amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 10.44 (s, 1H), 8.61 (s, 1H), 8.21 (s, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.80 (s, 1H), 6.86 (d, J = 2.2 Hz, 1H), 4.25 (q, J = 7.3 Hz, 2H), 3.39 (s, 3H), 2.07 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 468. M14

N-(5-(1-ethyl-1H- pyrazol-3-yl)-4-((3-(2- methoxyethoxy)-5- (methylsulfonyl)phenyl) amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (s, 1H), 10.37 (s, 1H), 8.58 (s, 1H), 8.21 (s, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.40 (s, 1H), 7.20 (s, 1H), 7.13 (s, 1H), 6.88 (d, J = 2.2, 1H), 4.29-4.24 (m, 4H), 3.69 (s, 2H), 3.32 (s, 3H), 3.29 (s, 3H), 2.06 (s, 3H), 1.45 (t, J = 7.3 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 474. M15

N-(5-(1-ethyl-1H- pyrazol-3-yl)-4-((3-(2- hydroxyethoxy)-5- (methylsulfonyl)phenyl) amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 1H), 10.31 (s, 1H), 8.57 (s, 1H), 7.91 (s, 1H), 7.41 (s, 1H), 7.20 (s, 1H), 7.19 (s, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 4.26 (q, J = 7.4 Hz, 2H), 4.30-4.20 (m, 2H), 3.80-3.70 (m, 2H), 3.29 (s, 3H), 2.08 (s, 3H), 1.45 (t, J = 7.4 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 460. M16

N-(4-((3- (cyclopropylmethoxy)- 5- (methylsulfonyl)phenyl) amino)-5-(1-ethyl-1H- pyrazol-3-yl)pyridin-2- yl)acetamide 1H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H), 10.36 (s, 1H), 8.58 (s, 1H), 8.20 (s, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.37 (s, 1H), 7.18 (s, 1H), 7.10 (s, 1H), 6.88 (d, J = 2.2 Hz, 1H), 4.30-4.25 (m, 2H), 3.96 (d, J = 6.9 Hz, 2H), 3.28 (s, 3H), 2.06 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H), 1.30-1.23 (m, 1H), 0.62-0.54 (m, 2H), 0.41-0.31 (m, 2H). MS (ESI) m/e [M + 1]⁺ 470. M17

N-(4-((4- (cyclopentyloxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1-ethyl- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.43 (s, 1H), 10.43 (s, 1H), 9.16 (s, 1H), 8.64 (s, 1H), 7.94 (s, 1H), 7.05 (s, 1H), 6.92 (d, J = 2.4 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 5.13-5.05 (m, 1H), 4.38-4.22 (m, 2H), 3.45 (s, 3H), 2.10 (s, 3H), 2.03- 1.94 (m, 2H), 1.89-1.68 (m, 4H), 1.67- 1.62 (m, 2H), 1.50 (t, J = 7.2 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 485. M18

N-(4-((4-ethoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1-ethyl- 1H-pyrazol-3- y)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.42 (s, 1H), 10.45 (s, 1H), 9.16 (s, 1H), 8.64 (s, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H), 6.93 (d, J = 2.2 Hz, 1H), 6.75 (s, 1H), 4.32-4.30 (m, 2H), 4.29- 4.23 (m, 2H), 3.46 (s, 3H), 2.11 (s, 3H), 1.50 (t, J = 7.2 Hz, 3H), 1.38 (t, J = 6.9 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 445. M19

N-(5-(1-ethyl-1H- pyrazol-3-yl)-4-((4-(2- hydroxyethoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.41 (s, 1H), 10.44 (s, 1H), 9.16 (s, 1H), 8.64 (s, 1H), 7.95 (s, 1H), 7.13 (s, 1H), 6.93 (d, J = 2.8 Hz, 1H), 6.77 (d, J = 2.8 Hz, 1H), 4.99 (t, 1H), 4.36-4.28 (m, 2H), 4.30-4.20 (m, 2H), 3.80-3.70 (m, 2H), 3.46 (s, 3H), 2.11 (s, 3H), 1.50 (t, J = 7.3 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 461. M20

N-(5-(1-ethyl-1H- pyrazol-3-yl)-4-((4-(2- methoxyethoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.46 (s, 1H), 10.60 (s, 1H), 9.10 (s, 1H), 8.64 (s, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.16 (s, 1H), 6.93 (s, 1H), 6.81 (d, J = 2.2 Hz, 1H), 4.37-4.31 (m, 4H), 3.75-3.71 (m, 2H), 3.45 (s, 3H), 3.32 (s, 3H), 2.12 (s, 3H), 1.50 (t, J = 7.2 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 475. M21

N-(5-(1-ethyl-1H- pyrazol-3-yl)-4-((3- isopropoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H), 10.43 (s, 1H), 9.24 (s, 1H), 8.63 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H), 6.70 (d, J = 2.3 Hz, 1H), 4.99-4.86 (m, 1H), 4.39-4.23 (m, 2H), 3.39 (s, 3H), 2.10 (s, 3H), 1.49-1.45 (m, 6H), 1.45- 1.40 (m, 3H). MS (ESI) m/e [M + 1]⁺ 459. M22

N-(5-(1-isopropyl-1H- pyrazol-3-yl)-4-((6- (methylsulfonyl)pyridin- 2-yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.65 (s, 1H), 10.46 (s, 1H), 9.26 (s, 1H), 8.68 (s, 1H), 8.04-7.99 (m, 2H), 7.58 (d, J = 7.0 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 6.95 (s, 1H), 4.72-4.69 (m, 1H), 3.49 (s, 3H), 2.12 (s, 3H), 1.54 (d, J = 6.6 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 415. M23

N-(4-((4-isopropoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- isopropyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.52 (s, 1H), 10.49 (s, 1H), 9.13 (s, 1H), 8.65 (s, 1H), 7.98 (d, J = 2.3 Hz, 1H), 7.07 (s, 1H), 6.93 (d, J = 2.3 Hz, 1H), 6.68 (s, 1H), 4.89-4.82 (m, 1H), 4.69-4.62 (m, 1H), 3.46 (s, 3H), 2.11 (s, 3H), 1.54 (d, J = 6.6 Hz, 6H), 1.35 (d, J = 5.8 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 473. M24

N-(5-(1-isopropyl-1H- pyrazol-3-yl)-4-((4-(2- methoxyethoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.49 (s, 1H), 10.48 (s, 1H), 9.12 (s, 1H), 8.65 (s, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.14 (s, 1H), 6.94 (d, J = 2.5 Hz, 1H), 6.75 (s, 1H), 4.75-4.70 (m, 1H), 4.38-4.33 (m, 2H), 3.75-3.70 (m, 2H), 3.45 (s, 3H), 3.32 (s, 3H), 2.11 (s, 3H), 1.54 (d, J = 6.5 Hz, 6H). MS (ESI) m/e [M + H]⁺ 489. M25

N-(5-(1-isopropyl-1H- pyrazol-3-yl)-4-((3- (methylsulfonyl)-5- (trifluoromethyl)phenyl) amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.58 (s, 1H), 10.52 (s, 1H), 8.63 (s, 1H), 8.23 (s, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.90 (d, J = 2.5 Hz, 1H), 7.81 (s, 1H), 6.88 (d, J = 2.5 Hz, 1H), 4.65-4.61 (m, 1H), 3.39 (s, 3H), 2.08 (s, 3H), 1.48 (d, J = 6.5 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 482. M26

N-(4-((3-isopropoxy-5- (methylsulfonyl)phenyl) amino)-5-(1-isopropyl- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.53 (s, 1H), 10.48 (s, 1H), 8.58 (s, 1H), 8.13 (s, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.39 (s, 1H), 7.14 (s, 1H), 7.10 (s, 1H), 6.89 (d, J = 2.5 Hz, 1H), 4.78-4.75 (m, 1H), 4.65- 4.61 (m, 1H), 3.29 (s, 3H), 2.08 (s, 3H), 1.49 (d, J = 6.6 Hz, 6H), 1.32 (d, J = 5.9 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 473. M27

N-(5-(1-isopropyl-1H- pyrazol-3-yl)-4-((3- methoxy-5- (methylsulfonyl)phenyl) amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.58 (s, 1H), 10.49 (s, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.39 (s, 1H), 7.23 (s, 1H), 7.14 (s, 1H), 6.89 (d, J = 2.2 Hz, 1H), 4.65-4.62 (m, 1H), 3.89 (s, 3H), 3.29 (s, 3H), 2.08 (s, 3H), 1.49 (d, J = 6.6 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 444. M28

N-(4-((4-(2- hydroxyethoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- isopropyl-1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.54 (s, 1H), 10.38 (s, 1H), 8.58 (s, 1H), 7.90- 7.80 (m, 1H), 7.40 (s, 1H), 7.19 (s, 1H), 7.14 (s, 1H), 6.95-6.88 (m, 1H), 4.95 (s, 1H), 4.70-4.60 (m, 1H), 4.20-4.15 (m, 2H), 3.80-3.70 (m, 2H), 3.29 (s, 3H), 2.08 (s, 3H), 1.49 (d, J = 6.5 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 475. M29

N-(4-((3-(2- hydroxyethoxy)-5- (methylsulfonyl)phenyl) amino)-5-(1-isopropyl- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.54 (s, 1H), 10.38 (s, 1H), 8.58 (s, 1H), 8.25- 8.20 (m, 1H), 7.95 (s, 1H), 7.40 (s, 1H), 7.19-7.14 (m, 2H), 6.89 (s, 1H), 5.02- 4.83 (m, 1H), 4.65-4.63 (m, 1H), 4.13- 4.10 (m, 2H), 3.76-3.74 (m, 2H), 3.29 (s, 3H), 2.08 (s, 3H), 1.49 (d, J = 6.5 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 474. M30

N-(4-((3- (methylsulfonyl)phenyl) amino)-5-(1- (tetrahydrofuran-3-yl)- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide MS (ESI): m/e [M + 1]⁺ 442. M31

N-(4-((4-methyl-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- (tetrahydrofuran-3-yl)- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 457. M32

(R)-N-(4-((3- (methylsulfonyl)-5- (trifluoromethyl)phenyl) amino)-5-(1- (tetrahydrofuran-3-yl)- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 510. M33

(S)-N-(4-((4- isopropoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- (tetrahydrofuran-3-yl)- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 501. M34

(R)-N-(4-((4- isopropoxy-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- (tetrahydrofuran-3-yl)- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide Molecular Weight: 501 MS (ESI) m/e [M + 1]⁺ 502. M35

(R)-N-(4-((4-methoxy- 6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- (tetrahydrofuran-3-yl)- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 473.

Example N1: Synthesis of N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

Step 1: tert-butyl (2-chloro-5-(1,5-dimethyl-1H-pyrazol-3-yl)pyridin-4-yl)carbamate

A mixture of tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (5.0 g, 16.3 mmol), 1,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.58 g, 16.28 mmol), Pd(PPh₃)₂Cl₂ (595 mg, 0.81 mmol), H₂O (1.0 mL) in dioxane (100 mL) was stirred at 100° C. for 4 h under nitrogen atmosphere. After cooled to room temperature, the mixture was filtrated and the filtration was concentrated under vacuum to give the residue, then purified by silica gel column chromatography using EA/PE (0-20%) to give tert-butyl (2-chloro-5-(1,5-dimethyl-1H-pyrazol-3-yl)pyridin-4-yl)carbamate (3.5 g, 67.3%). MS (ESI) m/e [M+1]⁺ 323.

Step 2: tert-butyl (2-acetamido-5-(1,5-dimethyl-1H-pyrazol-3-yl)pyridin-4-yl)carbamate

A mixture of tert-butyl (2-chloro-5-(1,5-dimethyl-1H-pyrazol-3-yl)pyridin-4-yl)carbamate (3.0 g, 9.23 mmol), acetamide (1.08 g, 18.5 mmol), Cs₂CO₃ (6.0 g, 18.5 mmol), Xant-Phos (1.06 g, 1.85 mmol) and Pd₂(dba)₃ (875 mg, 0.0.92 mmol) in dioxane (100 mL) was stirred at 110° C. for 12 h under nitrogen atmosphere. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with 20 mL of water. The resulting solution was extracted with EA (30 mL×3) and the combined organic layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography using PE/EA (20-50%) to give tert-butyl (2-acetamido-5-(1,5-dimethyl-1H-pyrazol-3-yl)pyridin-4-yl)carbamate (2.2 g, 69.2%). MS (ESI) m/e [M+1]⁺ 345.

Step 3: N-(4-amino-5-(1,5-dimethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide

A mixture of tert-butyl (2-acetamido-5-(1,5-dimethyl-1H-pyrazol-3-yl)pyridin-4-yl)carbamate (2.2 g, 6.38 mmol) in TFA (20 mL) and DCM (10 mL) was stirred at room temperature for 16 h. Upon completion of the reaction, the solvent was removed in vacuo and the residue diluted with water. NaHCO₃ (40 mL) was added to adjust the pH value to 9 and the resulting solution was extracted with EA (10 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated in vacuo to give N-(4-amino-5-(1,5-dimethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide (1.2 g, 76.9%). MS (ESI) m/e [M+1]⁺ 246.

Step 4: N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl) acetamide

A mixture of N-(4-amino-5-(1,5-dimethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide (50 mg, 0.20 mmol), 2-bromo-6-(methylsulfonyl)pyridine (58 mg, 0.24 mmol), Pd₂(dba)₃ (19 mg, 0.020 mmol), BINAP (13 mg, 0.020 mmol) and Cs₂CO₃ (200 mg, 0.61 mmol) in dioxane (5 mL) was stirred for 16 h at 120° C. under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (MeOH/DCM=0-10%) to give the crude product. The crude product was suspended in acetonitrile to give N-(5-(1,5-dimethyl-NH-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide (7.66 mg, 9.6%) ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 10.42 (s, 1H), 9.26 (s, 1H), 8.57 (s, 1H), 8.07-7.89 (i, 1H), 7.55 (d, J=7.2 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 6.71 (s, 1H), 3.89 (s, 3H), 3.48 (s, 3H), 2.32 (s, 3H), 2.09 (s, 3H). MS (ESI) m/e [M+1]⁺ 401.

The following Examples were prepared in a similar manner to the product Example N1:

¹H NMR and LC/MS Example Compound Chemical Name m/z (M + 1) N2

N-(5-(1,5-dimethyl- 1H-pyrazol-3-yl)-4- ((4-isopropoxy-6- (methylsulfonyl)pyridin- 2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.39 (s, 1H), 10.43 (s, 1H), 9.15 (s, 1H), 8.56 (s, 1H), 7.08 (s, 1H), 6.77 (s, 1H), 6.71 (s, 1H), 4.95- 4.90 (m, 1H), 3.90 (s, 3H), 3.46 (s, 3H), 2.33 (s, 3H), 2.10 (s, 3H), 1.34 (d, J = 5.7 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 459. N3

N-(5-(1,5-dimethyl- 1H-pyrazol-3-yl)-4- ((3-(2- hydroxyethoxy)-5- (methylsulfonyl)phenyl) amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (s, 1H), 10.39 (s, 1H), 8.49 (s, 1H), 8.10 (s, 1H), 7.41 (s, 1H), 7.22 (s, H), 7.14 (s, H), 6.66 (s, 1H), 4.95 (s, 1H), 4.20-4.10 (m, 2H), 3.84 (s, 3H), 3.80-3.70 (m, 2H), 3.30 (s, 3H), 2.32 (s, 3H), 2.07 (s, 3H). MS (ESI) m/e [M + 1]⁺ 460. N4

N-(5-(1,5-dimethyl- 1H-pyrazol-3-yl)-4- ((4-methoxy-6- (methylsulfonyl)pyridin- -2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.49 (s, 1H), 10.46 (s, 1H), 9.22 (s, 1H), 8.61 (s, 1H), 7.18 (s, 1H), 6.85 (s, 1H), 6.76 (s, 1H), 4.02 (s, 3H), 3.96 (s, 3H), 3.52 (s, 3H), 2.39 (s, 3H), 2.16 (s, 3H). MS (ESI) m/e [M + 1]⁺ 431. N5

N-(5-(1,5-dimethyl- 1H-pyrazol-3-yl)-4- ((4-(2- methoxyethoxy)-6- (methylsulfonyl)pyridin- 2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.48 (s, 1H), 10.46 (s, 1H), 9.23 (s, 1H), 8.61 (s, 1H), 7.19 (s, 1H), 6.86 (s, 1H), 6.76 (s, 1H), 4.45- 4.40 (m, 2H), 3.97 (s, 3H), 3.80- 3.75 (m, 2H), 3.63 (s, 3H), 3.52 (s, 3H), 2.39 (s, 3H), 2.16 (s, 3H). MS (ESI) m/e [M + 1]⁺ 475. N6

(R)-N-(5-(1,5- dimethyl-1H-pyrazol- 3-yl)-4-((4-(2- methoxypropoxy)-6- (methylsulfonyl)pyridin- 2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.40 (s, 1H), 10.42 (s, 1H), 9.17 (s, 1H), 8.56 (s, 1H), 7.14 (s, 1H), 6.83 (s, 1H), 6.71 (s, 1H), 4.27- 4.13 (m, 2H), 3.91 (s, 3H), 3.72- 3.71 (m, 1H), 3.46 (s, 3H), 3.34 (s, 3H), 2.34 (s, 3H), 2.10 (s, 3H), 1.20 (d, J = 6.2 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 489. N7

N-(5-(1,5-dimethyl- 1H-pyrazol-3-yl)-4- ((4-ethoxy-6- (methylsulfonyl)pyridin- 2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.41 (s, 1H), 10.39 (s, 1H), 9.16 (s, 1H), 8.55 (s, 1H), 7.15 (s, 1H), 6.77 (s, 1H), 6.70 (s, 1H), 4.27 (q, J = 6.9 Hz, 2H), 3.57 (s, 3H), 3.46 (s, 3H), 2.33 (s, 3H), 2.10 (s, 3H), 1.38 (t, J = 6.9 Hz, 3H). MS (ESI) m/e [M + 1]⁺ 445.

Example O1: Synthesis of N-(5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

Step 1: ethyl 3,5-dibromo-1H-pyrazole-4-carboxylate

To a solution of ethyl 1H-pyrazole-4-carboxylate (10.0 g, 71.4 mmol) in EtOH (200 mL) was added NaOAc (41.0 g, 500 mmol) in H₂O (300 mL) and then added Br₂ (45.6 g, 285 mmol) at 0° C. and the resulting mixture was stirred for 5 h at room temperature under nitrogen atmosphere. Upon completion of the reaction, the mixture was poured into water (100 mL) and extracted with EA (300 mL×2). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated to give the residue, and purified by silica gel column chromatography (PE/EA=100/1 to 0/1) to give ethyl 3,5-dibromo-1H-pyrazole-4-carboxylate (10.0 g, 47% yield). MS(ESI) m/e [M+1]⁺ 298.

Step 2: ethyl 3,5-dibromo-1-methyl-1H-pyrazole-4-carboxylate

To a solution of ethyl 3,5-dibromo-1H-pyrazole-4-carboxylate (10.0 g, 33.6 mmol) in THF (100 mL) was added NaH (60% in mineral oil, 2.0 g, 50 mmol) at 0° C. and the resulting mixture was stirred at this temperature for 30 min, then Mel (5.7 g, 40.0 mmol) was added at 0° C. and the resulting mixture was stirred for 6 h at room temperature under nitrogen atmosphere. Upon completion of the reaction, the mixture was poured into water (50 mL) and the resulting mixture was extracted with EA (60 mL×2). The combined organic phase was washed with brine, dried over Na₂SO₄, concentrated under vacuum. The residue was purified by silica gel column chromatography (PE/EA=50/1 to 0/1) to give ethyl 3,5-dibromo-1-methyl-1H-pyrazole-4-carboxylate (5.1 g, 51%). MS(ESI) m/e [M+1]⁺ 312.

Step 3: ethyl 3-bromo-1-methyl-5-morpholino-1H-pyrazole-4-carboxylate

To a solution of ethyl 3,5-dibromo-1-methyl-1H-pyrazole-4-carboxylate (4.0 g, 12.8 mmol) in NMP (50 mL) were added morpholine (1.7 g, 19.2 mmol) and K₂CO₃ (4.4 g, 32.0 mmol), the resulting mixture was heated to 130° C. stirred for 25 h under nitrogen atmosphere. After cooled to room temperature, the solvent was removed and the residue was diluted with water (20 mL) then extracted with EA (30 mL×3), the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (PE/EA=100/1 to 0/1) to give ethyl 3-bromo-1-methyl-5-morpholino-1H-pyrazole-4-carboxylate (2.5 g, 62%). ¹H NMR (CDCl₃) δ 4.40-4.35 (m, 2H), 3.79-3.75 (m, 4H), 3.73 (s, 3H), 3.15-3.10 (m, 4H), 1.40 (t, J=7.0 Hz, 3H). MS(ESI) m/e [M+1]⁺ 318.

Step 4: 4-(3-bromo-1-methyl-1H-pyrazol-5-yl)morpholine

To a solution of ethyl 3-bromo-1-methyl-5-morpholino-1H-pyrazole-4-carboxylate (2.5 g, 7.9 mmol) in EtOH (20 mL) was added NaOH (1.0 g, 25.1 mmol) in water (15 mL) and the resulting mixture was stirred for 3 h at 70° C. under nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled down to 0° C. and H₂SO₄ (6.2 g, 62.8 mmol) was added, then the mixture was stirred for another 5 h at 70° C. under nitrogen atmosphere. After cooled to room temperature, the mixture was poured into water (10 mL) and sat Na₂CO₃ water solution was added to adjust the pH value to 8, the resulting mixture was extracted with EA (30 mL×2). The combined organic layer was washed with brine, dried over Na₂SO₄, concentrated under vacuum. The residue was purified by silica gel column chromatography (PE/EA=50/1 to 0/1) to give 4-(3-bromo-1-methyl-1H-pyrazol-5-yl)morpholine (1.2 mg, 62%). MS(ESI) m/e [M+1]⁺ 246.

Step 5: (1-methyl-5-morpholino-1H-pyrazol-3-yl)boronic acid

To a solution of 4-(3-bromo-1-methyl-1H-pyrazol-5-yl)morpholine (1.1 g, 4.47 mmol) in 1,4-dioxane (10 mL) was added Pin₂B₂ (1.7 g, 6.7 mmol), Pd(dppf)Cl₂·CH₂Cl₂ (365 mg, 450 umol) and AcOK (1.7 g, 17.9 mmol), the resulting mixture was heated up to 100° C. and stirred at this temperature for 5 h. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with 20 mL of water. The resulting solution was extracted with 3×50 mL of EA and the combined organic layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give the crude product (1-methyl-5-morpholino-1H-pyrazol-3-yl)boronic acid and used directly for next step without purification. Ms (ESI) m/e [M+1]⁺ 212.

Step 6: tert-butyl (2-chloro-5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)pyridin-4-yl)carbamate

To a solution of tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (1.5 g, 4.9 mmol) in 1,4-dioxane (10 mL) were added (1-methyl-5-morpholino-1H-pyrazol-3-yl)boronic acid (1.0 g, 4.9 mmol), Pd(dppf)Cl₂ (358.0 mg, 490 umol) and K₃PO₄ (4.1 g, 19.5 mmol), the resulting mixture was heated up to 100° C. and stirred for 12 h at this temperature under nitrogen atmosphere. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with 20 mL of water. The resulting solution was extracted with 3×30 mL of EA and the combined organic layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE/EA=100/1 to 0/1) to give tert-butyl (2-chloro-5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)pyridin-4-yl)carbamate (1.0 g, 52%). ¹H NMR (CDCl₃) δ 10.95 (s, 1H) 8.46 (s, 1H) 8.38 (s, 1H) 6.19 (s, 1H) 3.89-3.85 (m, 4H) 3.81 (s, 3H) 3.02-2.96 (m, 4H) 1.56 (s, 9H). MS(ESI) m/e [M+1]⁺ 394.

Step 7: tert-butyl (2-acetamido-5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)pyridin-4-yl)carbamate

To a solution of tert-butyl (2-chloro-5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)pyridin-4-yl)carbamate (1.0 g, 2.5 mmol) in 1,4-dioxane (30 mL) was added acetamide (450.0 mg, 7.6 mmol), Pd₂(dba)₃ (228.0 mg, 250.0 umol), Xantphos (144.0 mg, 250.0 umol) and Cs₂CO₃ (2.5 g, 7.6 mmol). The resulting mixture was heated up to 110° C. and stirred for 10 h at this temperature under nitrogen atmosphere. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of EA and the combined organic layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE/EA=100/1 to 0/1) to give tert-butyl (2-acetamido-5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)pyridin-4-yl)carbamate (750 mg, 70% yield). MS(ESI) m/e [M+1]⁺ 417.

Step 8: N-(4-amino-5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)pyridin-2-yl)acetamide

To a solution of tert-butyl (2-acetamido-5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)pyridin-4-yl)carbamate (750 mg, 1.8 mmol) in DCM (2 mL) was added TFA (2 mL) and the resulting mixture was stirred at 40° C. for 5 h. After cooled to room temperature, the solvent was removed in vacuo and the residue was diluted with 20 mL of water. Then aqueous Na₂CO₃ was added to adjust the pH value to 8 and the resulting mixture was extracted with EA (10 mL×3). The combined organic layer was washed with brine (5 mL), dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA=100/1 to 0/1) to give N-(4-amino-5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)pyridin-2-yl)acetamide (480 mg, 80% yield). ¹H NMR (DMSO-d₆) δ 10.06 (s, 1H), 8.25 (s, 1H), 7.45 (s, 1H), 7.13 (s, 2H), 6.38 (s, 1H), 3.78-3.73 (m, 4H), 3.68 (s, 3H), 2.95-2.90 (m, 4H), 2.04 (s, 3H). MS(ESI) m/e [M+1]⁺ 317.

Step 9: N-(5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

To a mixture of N-(4-amino-5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)pyridin-2-yl)acetamide (100 mg, 0.32 mmol), 2-bromo-6-(methylsulfonyl)pyridine (90 mg, 0.38 mmol), Pd₂dba₃ (30 mg, 0.032 mmol), BINAP (40 mg, 0.064 mmol) and Cs₂CO₃ (205 mg, 0.64 mmol) in dioxane (10 mL) was stirred at 100° C. for 4 h. The mixture was filtrated and the filtrate as concentrated to give the residue and purified by Prep-TLC (MeOH/DCM=1:15) to afford N-(5-(1-methyl-5-morpholino-0H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyri dine-2-yl)amino)pyridin-2-yl)acetamide (75 mg, 52.8% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.71 (s, HH), 10.47 (s, 1H), 9.28 (s, 1H), 863 (s, 1H), 8.05-8.001 (m, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.36 (d, J=8.6 Hz, 1H), 6.63 (s, 1H), 3.84 (s, 3H), 3.79-3.77 (m, 4H), 3.50 (s, 3H), 2.99-2.96 (m, 4H), 2.11 (s, 3H). MS (ESI) m/e [M+1]⁺ 472.

The following Examples were prepared in a similar manner to the product Example O1:

¹H NMR and LC/MS Example Compound Chemical Name m/z (M + 1) O2

N-(4-((4-(2- methoxyethoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-5-morpholino- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.46 (s, 1H), 10.45 (s, 1H), 9.18 (s, 1H), 8.60 (s, 1H), 7.14 (s, 1H), 6.80 (s, 1H), 6.61 (s, 1H), 4.35-4.33 (m, 2H), 3.84 (s, 3H), 3.77-3.75 (m, 4H), 3.71-3.69 (m, 2H), 3.46 (s, 3H), 3.34 (s, 3H), 2.96-2.94 (m, 4H), 2.10 (s, 3H). MS (ESI) m/e [M + 1]⁺ 546. O3

N-(4-((4-(2- hydroxypropoxy)-6- (methylsulfonyl)pyridin- 2-yl)amino)-5-(1- methyl-5-morpholino- 1H-pyrazol-3- yl)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.43 (s, 1H), 10.46 (s, 1H), 9.15 (s, 1H), 8.58 (s, 1H), 7.12 (s, 1H), 6.78 (s, 1H), 6.59 (s, 1H), 4.06-4.00 (m, 3H), 3.85-3.81 (m, 3H), 3.76-3.74 (m, 4H), 3.44 (s, 3H), 2.95-2.93 (m, 4H), 2.08 (s, 3H), 1.26-1.14 (m, 2H). MS (ESI) m/e [M + 1]⁺ 546.

Example Q1: Synthesis of N-(5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridine-2-yl)amino)pyridin-2-yl)acetamide

Step 1: 2-chloro-5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-4-amine

A mixture of 6-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (1 g, 4.63 mmol), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (1.29 g, 5n10 mmol), Pd(dppf)Cl₂ (338 mg, 0.46 mmol) and K₂CO₃ (958 mg, 6.95 mmol) in 1,4-dioxane (20 mL) and H₂ (2 mL) was charged with nitrogen and heated to 100° C. stirred for 2 h. The reaction was cooled to room temperature and diluted with EA, washed with brine, dried and concentrated. The residue was applied onto a silica gel column with MeOH/DCM (1:100) to afford 2-chloro-5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-4-amine (141 g). MS (ESI) m/e [M+1]⁺ 264.

Step 2: N-(4-amino-5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide

A mixture of 2-chloro-5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-4-amine (528 mg, 2 mmol), acetamide (710 mg, 12 mmol), Pd₂dba₃ (180 mg, 02 mmol), Xantphos (230 mg, 0.4 mmol) and Cs₂CO₃ (1.3 g, 4 mmol) in 1,4-dioxane (10 mL) was heated to 130° C. in a sealed tube stirring overnight under nitrogen atmosphere. The reaction was cooled to room temperature, filtered and the filtration was concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (100:1) to afford crude N-(4-amino-5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (575 mg). MS (ESI) m/e [M+1]⁺ 287.

Step 3: N-(5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyri din-2-yl)amino)pyridin-2-yl)acetamide

A mixture of N-(4-amino-5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (50 mg, 0.17 mmol), 2-bromo-4-isopropoxy-6-(methylsulfonyl)pyridine (77 mg, 0.26 mmol), Pd₂dba₃ (16 mg, 0.017 mmol), BINAP (21 mg, 0.034 mmol) and Cs₂CO₃ (111 mg, 0.34 mmol) in 1,4-dioxane (6 mL) was heated to 130° C. in a sealed tube stirring for 5 h under nitrogen atmosphere. The reaction was cooled to room temperature, filtered and the filtration was concentrated under vacuum. The residue was applied onto Prep-TLC with DCM/MeOH (20:1) to afford N-(5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-isopropoxy-6-(methyl sulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide (17 mg, 20%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 10.49 (s, 1H), 9.03 (s, 1H), 8.61 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.08 (s, 1H), 6.59 (s, 1H), 4.85-4.80 (m, 1H), 4.55-4.52 (m, 2H), 4.36-4.32 (m, 2H), 3.42 (s, 3H), 2.11 (s, 3H), 1.34 (d, J=4.9 Hz, 6H). MS (ESI) m/e [M+1]⁺ 500.

Example Q21: Synthesis of compound N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

Method A

Step 1: 1-(2,6-dibromopyridin-3-yloxy)-2-methylpropan-2-ol

Into a 100-mL round-bottom flask, were placed 2,6-dibromopyridin-3-ol (2.00 g, 7.90 mmol), DMF (30 mL), K₂CO₃ (3.28 g, 23.73 mmol), 2,2-dimethyloxirane (0.68 g, 9.43 mmol). The resulting solution was stirred for 5 hr at 100° C. in an oil bath. After cooled to room temperature, the resulting solution was diluted with 50 mL of H₂O, extracted with 3×30 mL of ethyl acetate and the organic layers were combined and concentrated. The residue was purified by combi-flash (EtOAc/PE=1:4) to give the product (2.2 g, 85% yield). LCMS (ESI, m/z) [M+1]⁺ 324.

Step 2: 6-bromo-2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine

Into a 100-mL round-bottom flask, were placed 1-[(2,6-dibromopyridin-3-yl)oxy]-2-methylpropan-2-ol (2.00 g, 6.15 mmol), DMF (30 mL). This was followed by the addition of NaH (0.49 g, 60% in mineral oil, 12.30 mmol) in portions at 0° C. The resulting solution was stirred for 3 hr at 90° C. in an oil bath. After cooled to room temperature, the reaction was then quenched by the addition of 50 mL of NH₄Cl (aq). The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers were combined and concentrated. The residue was purified by combi-flash (EtOAc/PE=1:6) to give the product (1.06 g, 71% yield).

¹H NMR (400 MHz, CD₃Cl) δ 7.06-7.02 (m, 2H), 4.08 (s, 2H), 1.38 (s, 6H). LCMS (ESI, m/z) [M+1]⁺ 244, 246.

Step 3: 2-chloro-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-4-amine

A solution of 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (626.8 mg, 2.46 mmol), 6-bromo-2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (500 mg, 2.05 mmol), Pd (dppf)Cl₂ (300 mg, 0.41 mmol), K3PO₄ (869.2 mg, 4.1 mmol) in dioxane (8 mL) and H₂O (2 mL) was stirred at 75° C. for 2 hours. The mixture was cooled to rt and extracted between EA and H₂O. The organic layer was concentrated. The crude product was purified by silica gel column chromatography (PE/EA=1:1) to give the desired product (440 mg, 73.57%). MS (ESI) m/e [M+1]⁺ 292.

Step 4: N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide

A solution of 2-chloro-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-4-amine (440 mg, 1.51 mmol), acetamide (445.4 mg, 7.54 mmol), Pd₂(dba)₃ (276.6 mg, 0.3 mmol), Xant-phos (349.5 mg, 0.6 mmol) and Cs₂CO₃ (984.5 mg, 3 mmol) in dioxane (20 mL) was stirred at 130° C. for 5 hours. The mixture was cooled to r.t and filtered through celite. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM/MeOH=20:1) to give the desired product (305 mg, 64.26%). MS (ESI) m/e [M+1]⁺ 315.

Step 5: N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

A solution of N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (50 mg, 0.16 mmol), 2-bromo-4-methyl-6-(methylsulfonyl)pyridine (48 mg, 0.19 mmol), Pd₂(dba)₃ (29.3 mg, 0.032 mmol), Xant-phos (37 mg, 0.064 mmol) and Cs₂CO₃ (104.3 mg, 0.32 mmol) in dioxane (3 mL) was stirred at 130° C. for 5 hours. The mixture was cooled to rt and the solid was removed by filtration. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM/MeOH=15:1) to give the desired product (22.37 mg, 28.91%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.97 (s, 1H), 10.47 (s, 1H), 9.11 (s, 1H), 8.63 (s, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.46-7.41 (m, 2H), 6.97 (s, 1H), 4.26 (s, 2H), 3.43 (s, 3H), 2.42 (s, 3H), 2.11 (s, 3H), 1.37 (s, 6H). MS (ESI) m/e [M+1]⁺ 484.

Method B

Step 1: 1-(2,6-dibromopyridin-3-yloxy)-2-methylpropan-2-ol

Into a 100-mL round-bottom flask, were placed 2,6-dibromopyridin-3-ol (2.00 g, 7.90 mmol), DMF (30 mL), K₂CO₃ (3.28 g, 23.73 mmol), 2,2-dimethyloxirane (0.68 g, 9.43 mmol). The resulting solution was stirred for 5 hr at 100° C. in an oil bath. After cooled to room temperature, the resulting solution was diluted with 50 mL of H₂O, extracted with 3×30 mL of ethyl acetate and the organic layers were combined and concentrated. The residue was purified by combi-flash (EtOAc/PE=1/4) to give the product (2.2 g, 85% yield). LCMS (ESI, m/z) [M+1]⁺ 324.

Step 2: 6-bromo-3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine and 6-bromo-2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 1-[(2,6-dibromopyridin-3-yl)oxy]-2-methylpropan-2-ol (1.00 g, 3.07 mmol) and THF (15 mL). This was followed by the addition of NaH (186 mg, 4.58 mmol, 60% wt) in portions at 0° C. The resulting solution was stirred for 16 hr at 55° C. After cooled to room temperature, 20 mL of NH₄Cl (aq) was added to quench the reaction and the resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers were combined and concentrated. The residue was purified by combi-flash (EtOAc/PE=0-35%) to give the product.

The mixture was separated by Chiral-Prep-HPLC with the following conditions, to obtain two resulted compounds: Column: CHIRAL ART Cellulose-SB, 3×25 cm, 5 um; Mobile Phase A: CO₂, Mobile Phase B: MeOH (0.1% 2M NH₃-MeOH); Flow rate: 60 mL/min; Gradient: 15% B; Column Temperature: 35° C.; Back Pressure: 100 bar; 220 nm. This resulted in 60 mg of 6-bromo-3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (RT₁: 3.94 min) and 210 mg of 6-bromo-2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (RT₂: 4.51 min).

6-Bromo-3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine: ¹H NMR (300 MHz, CD₃Cl) 57.06 (d, J=8.0 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 3.88 (s, 2H), 1.39 (s, 6H). ¹H NMR (400 MHz, DMSO-d₆) δ 7.30 (d, J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 3.99 (s, 2H), 1.32 (s, 6H); LCMS (ESI, m/z): [M+H]⁺ 244, 246.

6-bromo-2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine: ¹H NMR (300 MHz, CD₃Cl) δ 7.04-7.03 (m, 2H), 4.08 (s, 2H), 1.39 (s, 6H). LCMS (ESI, m/z): [M+H]⁺ 244, 246. And, the structure of the compound was further confirmed by single crystal structure determination.

Step 3: 2-chloro-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-4-amine

A solution of 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (626.8 mg, 2.46 mmol), 6-bromo-2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (500 mg, 2.05 mmol), Pd (dppf)Cl₂ (300 mg, 0.41 mmol), K₃PO₄ (869.2 mg, 4.1 mmol) in dioxane (8 mL) and H₂O (2 mL) was stirred at 75° C. for 2 hr. The mixture was cooled to rt and extracted between EA and H₂O. The organic layer was concentrated. The crude product was purified by silica gel column chromatography (PE/EA=1/1) to give the desired product (440 mg, 73.57%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (s, 1H), 7.40 (d, J=8.2 Hz, 2H), 7.33 (d, J=12.4 Hz, 2H), 6.64 (s, 1H), 4.12 (s, 2H), 1.28 (s, 6H). MS (ESI) m/e [M+1]⁺ 292.

Step 4: N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide

A solution of 2-chloro-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-4-amine (440 mg, 1.51 mmol), acetamide (445.4 mg, 7.54 mmol), Pd₂(dba)₃ (276.6 mg, 0.3 mmol), Xant-phos (349.5 mg, 0.6 mmol) and Cs₂CO₃ (984.5 mg, 3 mmol) in dioxane (20 mL) was stirred at 130° C. for 5 hours. The mixture was cooled to r.t and filtered through celite. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM/MeOH=20/1) to give the desired product (305 mg, 64.26%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.07 (s, 1H), 8.26 (s, 1H), 7.48-7.35 (m, 2H), 7.33-7.17 (m, 3H), 4.11 (s, 2H), 2.01 (s, 3H), 1.28 (s, 6H). MS (ESI) m/e [M+1]⁺ 315.

Step 5: N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

A solution of N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (50 mg, 0.16 mmol), 2-bromo-4-methyl-6-(methylsulfonyl)pyridine (48 mg, 0.19 mmol), Pd₂(dba)₃ (29.3 mg, 0.032 mmol), Xant-phos (37 mg, 0.064 mmol) and Cs₂CO₃ (104.3 mg, 0.32 mmol) in dioxane (3 mL) was stirred at 130° C. for 5 hours. The mixture was cooled to rt and the solid was removed by filtration. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM/MeOH=15/1) to give the desired product (22.37 mg, 28.91%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.97 (s, 1H), 10.47 (s, 1H), 9.11 (s, 1H), 8.63 (s, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.46-7.41 (m, 2H), 6.97 (s, 1H), 4.26 (s, 2H), 3.43 (s, 3H), 2.42 (s, 3H), 2.11 (s, 3H), 1.37 (s, 6H). MS (ESI) m/e [M+1]⁺ 484.

Example Q22: Synthesis of compound N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-morpholinopyridin-2-yl)amino)pyridin-2-yl)acetamide

A solution of N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (600 mg, 2 mmol), 4-(2-bromo-6-(methylsulfonyl)pyridin-4-yl)morpholine (964 mg, 3 mmol), Pd₂(dba)₃ (366 mg, 0.4 mmol), Xantphos (463 mg, 0.8 mmol) and Cs₂CO₃ (1304 mg, 4 mmol) in dioxane (30 mL) was stirred at 130° C. for 5 hours. The mixture was cooled to r.t and the solid was filtered through celite. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM/MeOH=15/1) to give the product (65.36 mg, 59%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.39 (s, 1H), 10.44 (s, 1H), 8.87 (s, 1H), 8.56 (s, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.10 (s, 1H), 6.52 (s, 1H), 4.24 (s, 2H), 3.77-3.68 (m, 4H), 3.41-3.36 (m, 4H), 3.35 (s, 3H), 2.09 (s, 3H), 1.36 (s, 6H). MS (ESI) m/e [M+1]⁺ 555.

Example Q23: Synthesis of compound N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

A solution of N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (60 mg, 0.2 mmol), 2-bromo-6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridine (96 mg, 0.3 mmol), Pd₂(dba)₃ (36.6 mg, 0.04 mmol), Xantphos (46.3 mg, 0.08 mmol) and Cs₂CO₃ (130.4 mg, 0.4 mmol) in dioxane (3 mL) was stirred at 130° C. for 5 hr. The mixture was cooled to RT and the solid was removed by filtration. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM/MeOH=15/1) to give the product (63.6 mg, 57%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.86 (s, 1H), 10.49 (s, 1H), 9.06 (s, 1H), 8.62 (s, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.52-7.38 (m, 2H), 7.05 (s, 1H), 4.26 (s, 2H), 4.01-3.92 (m, 2H), 3.49-3.44 (m, 2H), 3.43 (s, 3H), 3.02-2.89 (m, 1H), 2.11 (s, 3H), 1.84-1.74 (m, 2H), 1.72-1.59 (m, 2H), 1.37 (s, 6H). MS (ESI) m/e [M+1]⁺ 554.

Example Q24: Synthesis of compound N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(methoxy-d3)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

A solution of N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (60 mg, 0.2 mmol), 2-bromo-4-(methoxy-d3)-6-(methylsulfonyl)pyridine (80.7 mg, 0.3 mmol), Pd₂(dba)₃ (36.6 mg, 0.04 mmol), Xantphos (46.3 mg, 0.08 mmol) and Cs₂CO₃ (130.4 mg, 0.4 mmol) in dioxane (3 mL) was stirred at 130° C. for 5 hours. The mixture was cooled to RT and filtered through celite. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM/MeOH=15/1) to give the product (26.04 mg, 26%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.76 (s, 1H), 10.49 (s, 1H), 8.99 (s, 1H), 8.61 (s, 1H), 7.58 (d, J=8.3 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.12 (s, 1H), 6.68 (s, 1H), 4.25 (s, 2H), 3.41 (s, 3H), 2.11 (s, 3H), 1.36 (s, 6H). MS (ESI) m/e [M+1]⁺ 503.

Example Q25: synthesis of compound N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

A solution of N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (60 mg, 0.2 mmol), 2-bromo-4-methoxy-6-(methylsulfonyl)pyridine (79.8 mg, 0.3 mmol), Pd₂(dba)₃ (36.6 mg, 0.04 mmol), Xant-phos (46.3 mg, 0.08 mmol) and Cs₂CO₃ (130.4 mg, 0.4 mmol) in dioxane (3 mL) was stirred at 130° C. for 5 hr. The mixture was cooled to rt and filtered through celite. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM/MeOH=15/1) to give the product (25.21 mg, 25%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.77 (s, 1H), 10.49 (s, 1H), 8.99 (s, 1H), 8.61 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.12 (s, 1H), 6.69 (s, 1H), 4.25 (s, 2H), 3.93 (s, 3H), 3.41 (s, 3H), 2.11 (s, 3H), 1.36 (s, 6H). MS (ESI) m/e [M+1]⁺ 500.

Example Q26: synthesis of compound N-(4-((3,4-dimethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide

A solution of N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (60 mg, 0.2 mmol), 2-bromo-3,4-dimethoxy-6-(methylsulfonyl)pyridine (88.8 mg, 0.3 mmol), Pd₂(dba)₃ (36.6 mg, 0.04 mmol), Xant-phos (46.3 mg, 0.08 mmol) and Cs₂CO₃ (130.4 mg, 0.4 mmol) in dioxane (3 mL) was stirred at 130° C. for 5 hr. The mixture was cooled to rt and filtered through celite. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM/MeOH=15/1) to give the product (17.35 mg, 17%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.11 (s, 1H), 10.47 (s, 1H), 9.34 (s, 1H), 8.59 (s, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.37 (s, 1H), 4.28 (s, 2H), 4.01 (s, 3H), 3.95 (s, 3H), 3.48 (s, 3H), 2.12 (s, 3H), 1.37 (s, 6H). MS (ESI) m/e [M+1]⁺ 530.

Example Q35: Synthesis of compound (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methyl-morpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)-pyridin-2-yl)acetamide

N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyri-din-2-yl)acetamide (50 mg, 0.16 mmol), (S)-4-(2-chloro-6-(methylsulfonyl)pyridin-4-yl)-3-methyl-morpholine (50.8 mg, 0.18 mmol), Pd₂dba₃ (14.6 mg, 0.02 mmol), BINAP (20 mg, 0.03 mmol) and Cs₂CO₃ (78 mg, 0.24 mmol) were added into 1,4-dioxane (10 mL). The resulting mixture was degassed with nitrogen and heated to 130° C. with stirring for 2 hr. The reaction was cooled to room temperature. The solids were filtered out. The filtration was concentrated under vacuum. The residue was first applied onto Prep-TLC with DCM/MeOH (20/1) to give the product (65.71 mg, yield: 72.6%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.48 (s, 1H), 10.44 (s, 1H), 8.88 (s, 1H), 8.56 (s, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.06 (s, 1H), 6.45 (s, 1H), 4.24 (s, 2H), 4.03 (d, J=5.1 Hz, 1H), 3.99-3.90 (m, 1H), 3.70 (d, J=10.3 Hz, 2H), 3.52 (t, J=10.3 Hz, 2H), 3.36 (s, 3H), 3.16 (d, J=10.9 Hz, 1H), 2.10 (s, 3H), 1.36 (s, 6H), 1.16 (d, J=6.6 Hz, 3H). MS (ESI) m/e [M+1]⁺ 569.

Example Q36: Synthesis of compound (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methyl-morpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)-pyridin-2-yl)acetamide

N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyri-din-2-yl)acetamide (50 mg, 0.16 mmol), (R)-4-(2-chloro-6-(methylsulfonyl)pyridin-4-yl)-3-methyl-morpholine (50.8 mg, 0.18 mmol), Pd₂dba₃ (14.6 mg, 0.02 mmol), BINAP (20 mg, 0.03 mmol) and Cs₂CO₃ (78 mg, 0.24 mmol) were added into 1,4-dioxane (10 mL). The resulting mixture was degassed with nitrogen and heated to 130° C. with stirring for 2 hr. The reaction was cooled to room temperature. The solids were filtered out. The filtration was concentrated under vacuum. The residue was first applied onto Prep-TLC with DCM/MeOH (20/1) to give the product (49.19 mg, yield: 54.4%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.48 (s, 1H), 10.43 (s, 1H), 8.88 (s, 1H), 8.56 (s, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.05 (s, 1H), 6.45 (s, 1H), 4.23 (s, 2H), 4.03-4.01 (m, 1H), 3.95 (d, J=10.6 Hz, 1H), 3.69 (dd, J=11.4 Hz, 2H), 3.55-3.49 (m, 2H), 3.35 (s, 3H), 3.17 (t, J=11.4 Hz, 1H), 2.09 (s, 3H), 1.35 (s, 6H), 1.16 (d, J=4.1 Hz, 3H). MS (ESI) m/e [M+1]⁺ 569.

Example Q37: synthesis of compound N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(methoxy-d3)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

A mixture of N-(4-amino-5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (50 mg, 0.16 mmol), 2-bromo-4-(methoxy-d3)-6-(methylsulfonyl)pyridine (51 mg, 0.19 mmol), Pd₂(dba)₃ (15 mg, 0.016 mmol), BINAP (10 mg, 0.016 mmol) and Cs₂CO₃ (156 mg, 0.48 mmol) in dioxane (10 mL) was stirred for 5 h at 130° C. under nitrogen atmosphere. After cooled to room temperature, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (MeOH/DCM=0-10%) to give the product (29.01 mg, 36.4%). H NMR (400 MHz, DMSO-d₆) δ 12.03 (s, 1H), 10.44 (s, 1H), 8.93 (s, 1H), 8.57 (s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.03 (s, 1H), 6.57 (s, 1H), 4.01 (s, 2H), 3.35 (s, 3H), 2.05 (s, 3H), 1.33 (s, 6H). MS (ESI) m/e [M+1]⁺ 503.

Example Q38: synthesis of compound N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

A mixture of N-(4-amino-5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (50 mg, 0.16 mmol), 2-bromo-4-methoxy-6-(methylsulfonyl)pyridine (51 mg, 0.19 mmol), Pd₂(dba)₃ (15 mg, 0.016 mmol), BINAP (10 mg, 0.016 mmol) and Cs₂CO₃ (156 mg, 0.48 mmol) in dioxane (10 mL) was stirred for 5 h at 130° C. under nitrogen atmosphere After cooled to room temperature, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (MeOH/DCM=0-10%) to give the product (39.76 mg, 50.1%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 1H), 10.46 (s, 1H), 8.95 (s, 1H), 8.59 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.05 (s, 1H), 6.59 (s, 1H), 4.03 (s, 2H), 3.89 (s, 3H), 3.37 (s, 3H), 2.06 (s, 3H), 1.35 (s, 6H). MS (ESI) m/e [M+1]⁺ 500.

Example Q40: synthesis of compound N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

A mixture of N-(4-amino-5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (50 mg, 0.16 mmol), 2-chloro-6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridine (53 mg, 0.19 mmol), Pd₂(dba)₃ (15 mg, 0.016 mmol), BINAP (10 mg, 0.016 mmol) and Cs₂CO₃ (156 mg, 0.48 mmol) in dioxane (10 mL) was stirred for 5 h at 130° C. under nitrogen atmosphere. After cooled to room temperature, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (MeOH/DCM=0-10%) to give the product (33.12 mg, 37.7%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.43 (s, 1H), 10.45 (s, 1H), 9.04 (s, 1H), 8.62 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 6.94 (s, 1H), 4.04 (s, 2H), 3.93-3.90 (m, 2H), 3.44-3.40 (m, 5H), 2.91-2.90 (m, 1H), 2.07 (s, 3H), 1.80-1.77 (m, 2H), 1.63-1.57 (m, 2H), 1.36 (s, 6H). MS (ESI) m/e [M+1]⁺ 554.

Example Q43: synthesis of compound (S)—N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

Step 1. 2-chloro-5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-4-amine

A mixture of 6-bromo-3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (400 mg, 1.65 mmol), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (439 mg, 1.73 mmol), Pd(dppf)Cl₂ (120 mg, 0.16 mmol) and K₃PO₄ (1.05 g, 4.94 mmol) in dioxane (15 mL) and H₂O (3 mL) was stirred for 2 h at 90° C. under nitrogen atmosphere. After cooled to room temperature, the solid was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by combi-flash (EA/PE=0-60%) to give the product (450 mg, 94.1%). MS (ESI) m/e [M+1]⁺ 292.

Step 2. N-(4-amino-5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide

A mixture of 2-chloro-5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-4-amine (450 mg, 1.55 mmol), acetamide (639 mg, 10.8 mmol), Pd₂(dba)₃ (142 mg, 0.15 mmol), Xantphos (89 mg, 0.15 mmol) and Cs₂CO₃ (1.51 g, 4.64 mmol) in dioxane (15 mL) was stirred for 5 h at 130° C. under nitrogen atmosphere. After cooled to room temperature, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (MeOH/DCM=0-10%) to give the product (220 mg, 45.4%). MS (ESI) m/e [M+1]⁺ 315.

Step 3. (S)—N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

A mixture of N-(4-amino-5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (50 mg, 0.16 mmol), (S)-2-bromo-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine (56 mg, 0.19 mmol), Pd₂(dba)₃ (15 mg, 0.016 mmol), BINAP (10 mg, 0.016 mmol) and Cs₂CO₃ (156 mg, 0.48 mmol) in dioxane (10 mL) was stirred for 5 h at 130° C. under nitrogen atmosphere. After cooled to room temperature, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (MeOH/DCM=0-10%) to give the crude product. The crude product was washed with acetonitrile to give the product (7.29 mg, 8.7%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.26 (s, 1H), 10.47 (s, 1H), 9.05 (s, 1H), 8.61 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.05 (s, 1H), 4.45-4.44 (m, 1H), 4.04 (s, 2H), 3.41 (s, 3H), 3.22 (s, 3H), 2.07 (s, 3H), 1.40-1.29 (m, 9H). MS (ESI) m/e [M+1]⁺ 528.

Example Q46: synthesis of (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

Step 1: (S)-2,6-dichloro-4-(3-methoxypyrrolidin-1-yl)pyridine

To a round bottom flask was added 2,6-dichloro-4-iodopyridine (5.0 g, 18.3 mmol), (S)-3-methoxypyrrolidine (2.6 g, 19.2 mmol), Pd₂dba₃ (503 mg, 0.6 mmol), Xantphos (318 mg, 0.6 mmol), t-BuOK (4.4 g, 45.8 mmol) and 1,4-dioxane (100 mL). The resulting mixture was charged into nitrogen and heated to 40° C. with stirring for 13 h. The reaction was cooled to room temperature. Solids were filtered out. The filtration was concentrated. The residue was applied onto a silica gel column with EtOAc/PE to afford (S)-2,6-dichloro-4-(3-methoxypyrrolidin-1-yl)pyridine as dark brown oil (3.8 g, 84.4%). MS (ESI) m/e [M+1]⁺ 247.

Step 2: (S)-2-chloro-4-(3-methoxypyrrolidin-1-yl)-6-(methylthio)pyridine

To a solution of (S)-2,6-dichloro-4-(3-methoxypyrrolidin-1-yl)pyridine (3.6 g, 14.6 mmol) in DMF (40 mL) was added CH₃SNa (1.3 g, 17.6 mmol). The resulting reaction was heated to 100° C. with stirring for 2 hours. The reaction mixture was cooled to room temperature. The reaction was quenched by water/ice (200 mL). The resulting solution was extracted with EtOAc (40 mL×5). The organic layer was washed with water and brine, dried and concentrated. This resulted in 4.5 g of (S)-2-chloro-4-(3-methoxypyrrolidin-1-yl)-6-(methylthio)pyridine 4.5 g as yellow crude oil. MS (ESI) m/e [M+1]⁺ 259.

Step 3: (S)-2-chloro-4-(3-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridine

To a solution of (S)-2-chloro-4-(3-methoxypyrrolidin-1-yl)-6-(methylthio)py-ridine (4.5 g, 17.4 mmol) in MeOH (30 mL) was added a solution of Oxone (12.8 g, 20.8 mmol) in H₂O (30 mL) at room temperature dropwise with stirring. The resulting solution was stirred at room temperature for 1.5 h. The reaction was diluted with water (150 mL). The resulting solution was extracted with EtOAc (30 mL×5). The organic layer was washed with water and brine, dried and concentrated. The residue was applied onto a silica gel column with DCM/EtOAc (1:1). This resulted in 3.5 g of (S)-2-chloro-4-(3-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridine as a light yellow solid (Yield=78.1% for two steps). MS (ESI) m/e [M+1]⁺ 291.

Step 4: (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

(S)-2-chloro-4-(3-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridine (100 mg, 0.3 mmol), N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (102 mg, 0.35 mmol), Pd₂dba₃ (29.2 mg, 0.03 mmol), Xantphos (37 mg, 0.06 mmol) and K₃PO₄ (135 mg, 0.6 mmol) were added into 2-methyltetrahydrofuran (9.0 mL) and H₂O (1.0 mL). The resulting mixture was degassed with nitrogen and heated to 90° C. with stirring for 16 h. The reaction was cooled to room temperature. The solids were filtered out. The filtration was concentrated under vacuum. The residue was applied onto Prep-TLC with DCM/MeOH (17:1) to afford (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-metho-xypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide as a white solid (71.97 mg, yield: 40.0%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.48 (s, 1H), 10.45 (s, 1H), 8.85 (s, 1H), 8.57 (s, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 6.78 (s, 1H), 6.21 (s, 1H), 4.25 (s, 2H), 4.11 (s, 1H), 3.59-3.35 (m, 7H), 3.28 (s, 3H), 2.12-2.06 (m, 5H), 1.35 (s, 6H). MS (ESI) m/e [M+1]⁺ 569.

Example Q49: synthesis of N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methoxyazetidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

A mixture of N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (100 mg, 0.32 mmol), 2-chloro-4-(3-methoxyazetidin-1-yl)-6-(methylsulfonyl)pyridine (105 mg, 0.38 mmol), Pd₂(dba)₃ (29 mg, 0.032 mmol), BINAP (20 mg, 0.032 mmol) and Cs₂CO₃ (311 mg, 0.96 mmol) in 1,4-dioxane (10 mL) was stirred for 5 h at 130° C. under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (MeOH/DCM=0-10%) to give the crude product. The crude product was suspended in acetonitrile to give the product (46 mg, 26.4%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.43 (s, 1H), 10.40 (s, 1H), 8.79 (s, 1H), 8.52 (s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 6.58 (s, 1H), 6.01 (s, 1H), 4.33-4.32 (m, 1H), 4.19-4.18 (m, 4H), 3.81 (d, J=8.0 Hz, 2H), 3.29 (s, 3H), 3.21 (s, 3H), 2.05 (s, 3H), 1.31 (s, 6H). LCMS (ESI) m/e [M+1]⁺=555.

Example Q50: synthesis of (R/S)—N-(4-((4-(1,4-dioxan-2-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide

A mixture of N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (100 mg, 0.32 mmol), (R or S)-2-chloro-4-(1,4-dioxan-2-yl)-6-(methylsulfonyl)pyridine (98 mg, 0.35 mmol), Pd₂(dba)₃ (30 mg, 0.032 mmol), BINAP (20 mg, 0.032 mmol) and Cs₂CO₃ (312 mg, 0.96 mmol) in dioxane (10 mL) was stirred for 5 h at 130° C. under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (MeOH/DCM=0-10%) to give the crude product. The crude product was suspended in acetonitrile to give the product (32 mg, 17.9%). ¹H NMR (400 MHz, DMSO-do) δ 11.78 (s, 1H), 10.44 (s, 1H), 8.98 (s, 1H), 8.55 (s, 1H), 7.57-7.44 (m, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.12 (s, 1H), 4.71-4.70 (m, 1H), 4.19 (s, 2H), 3.90-3.88 (m, 2H), 3.78-3.66 (m, 2H), 3.54-3.53 (m, 1H), 3.36 (s, 3H), 3.23-3.19 (m, 1H), 2.04 (s, 3H), 1.30 (s, 6H). MS (ESI) m/e [M+1]⁺ 556.

Example Q51: synthesis of (S/R)—N-(4-((4-(1,4-dioxan-2-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide

A mixture of N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (50 mg, 0.15 mmol), (S or R)-2-chloro-4-(1,4-dioxan-2-yl)-6-(methylsulfonyl)pyridine (51 mg, 0.19 mmol), Pd₂(dba)₃ (15 mg, 0.015 mmol), BINAP (10 mg, 0.015 mmol) and Cs₂CO₃ (78 mg, 0.238 mmol) in dioxane (10 mL) was stirred for 5 h at 130° C. under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (MeOH/DCM=0-10%) to give the crude product. The crude product was suspended in acetonitrile to give the product (50 mg, 60%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (s, 1H), 10.46 (s, 1H), 9.00 (s, 1H), 8.57 (s, 1H), 7.60-7.45 (m, 2H), 7.39 (d, J=7.9 Hz, 1H), 7.14 (s, 1H), 4.72 (d, J=9.0 Hz, 1H), 4.21 (s, 2H), 3.96-3.88 (m, 2H), 3.82-3.67 (m, 2H), 3.58-3.55 (m, 1H), 3.38 (s, 3H), 2.06 (s, 3H), 1.32 (s, 6H). MS (ESI) m/e [M+1]⁺=556.

Example Q52: synthesis of N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(4-methoxypiperidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

A mixture of N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (100 mg, 0.32 mmol), 2-chloro-4-(4-methoxypiperidin-1-yl)-6-(methylsulfonyl)pyridine (116 mg, 0.38 mmol), Pd₂(dba)₃ (29 mg, 0.032 mmol), BINAP (20 mg, 0.032 mmol) and Cs₂CO₃ (311 mg, 0.96 mmol) in dioxane (10 mL) was stirred for 5 h at 130° C. under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (MeOH/DCM=0-10%) to give the crude product. The crude product was suspended in acetonitrile to give the product (41 mg, 22%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.35 (s, 1H), 10.37 (s, 1H), 8.81 (s, 1H), 8.49 (s, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.00 (s, 1H), 6.44 (s, 1H), 4.17 (s, 2H), 3.60-3.59 (m, 2H), 3.39-3.38 (m, 1H), 3.28 (s, 3H), 3.31-3.16 (m, 5H), 2.03 (s, 3H), 1.83-1.82 (m, 2H), 1.43-1.42 (m, 2H), 1.29 (s, 6H). MS (ESI) m/e [M+1]⁺ 583.

Example Q53: N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-((cis)-3-methoxycyclobutyl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

A mixture of N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (53 mg, 0.17 mmol), 2-bromo-4-((cis)-3-methoxycyclobutyl)-6-(methylsulfonyl)pyridine (47 mg, 0.17 mmol), Pd₂(dba)₃ (16 mg, 0.017 mmol), Xantphos (10 mg, 0.017 mmol), Cs₂CO₃ (110 mg, 0.34 mmol) in 5 mL 1,4-dioxane was stirred at 130° C. under nitrogen atmosphere for 2 h. After cooled to rt, the solution was concentrated in vacuo and the residue was purified by Prep TLC to give the product (20 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 11.85 (s, 1H), 10.50 (s, 1H), 9.06 (s, 1H), 8.61 (s, TH), 7.58 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.39 (s, 1H), 7.01 (s, 1H), 4.25 (s, 2H), 3.89 (m, 1H), 3.43 (s, 3H), 3.18 (m, 4H), 2.68 (m, 2H), 2.10 (s, 3H), 1.91 (m, 2H), 1.36 (s, 6H). MS (ESI) m/e [M+1]⁺=554.

Example Q54: Synthesis of N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-((trans)-3-methoxycyclobutyl--(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

This compound was synthesized by using the similar procedure as example Q53. ¹H NMR (400 MHz, DMSO-d₆) δ 11.95 (s, 1H), 10.50 (s, 1H), 9.07 (s, 1H), 8.63 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.43 (m, 2H), 7.06 (s, 1H), 4.25 (s, 2H), 4.12-3.97 (m, 1H), 3.71-3.56 (m, 1H), 3.44 (s, 3H), 3.19 (s, 3H), 2.43-2.32 (m, 4H), 2.11 (s, 3H), 1.36 (s, 6H). MS (ESI) m/e [M+1]⁺ 554.

Example Q55: Synthesis of N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(4-hydroxy-4-methylpiperidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

A mixture of N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (50 mg, 0.16 mmol), 1-(2-bromo-6-(methylsulfonyl)pyridin-4-yl)-4-methylpiperidin-4-ol (66 mg, 0.19 mmol), Pd₂(dba)₃ (7 mg, 0.008 mmol), XantPhos (9 mg, 0.016 mmol) and K₃PO₄ (68 mg, 0.32 mmol) in 2-MeTHF (5 mL) and water (0.5 mL) was stirred at 90° C. for 4 h under nitrogen atmosphere. After cooled to rt, the reaction mixture was concentrated and the residue was purified by Prep-TLC (MeOH:DCM=1:20) to give the product (39 mg, 42%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.42 (s, 1H), 10.46 (s, 1H), 8.86 (s, 1H), 8.55 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.06 (s, 1H), 6.50 (s, 1H), 4.47 (s, 1H), 4.24 (s, 2H), 3.61 (d, J=13.2 Hz, 2H), 3.37-3.34 (m, 5H), 2.10 (s, 3H), 1.57-1.49 (m, 4H), 1.36 (s, 6H), 1.15 (s, 3H). MS (ESI) m/e [M+H]⁺=583.

Example Q63: synthesis of N-(4-((4-cyano-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide

A mixture of N-(4-amino-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide (80 mg, 0.25 mmol), 2-bromo-6-(methylsulfonyl)isonicotinonitrile (80 mg, 0.31 mmol), Pd₂(dba)₃ (23 mg, 0.025 mmol), BINAP (16 mg, 0.025 mmol) and Cs₂CO₃ (249 mg, 0.76 mmol) in dioxane (10 mL) was stirred for 5 h at 130° C. under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (MeOH/DCM=0-10%) to give the crude product. The crude product was suspended in acetonitrile to give the product (11.09 mg). ¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 1H), 10.59 (s, 1H), 9.05 (s, 1H), 8.65 (s, 1H), 7.82 (s, 1H), 7.63-7.50 (m, 2H), 7.43 (d, J=8.0 Hz, 1H), 4.25 (s, 2H), 3.47 (s, 3H), 2.12 (s, 3H), 1.37 (s, 6H). MS (ESI) m/e [M+1]⁺ 495.

The following Examples were prepared in a similar manner to the product Example Q1:

¹H NMR and LC/MS Example Compound Chemical Name m/z (M + 1) Q2

N-(5-([1,3]dioxolo[4,5- b]pyridin-5-yl)-4-((4- isopropoxy-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 10.13 (s, 1H), 8.85 (s, 1H), 8.35 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 6.98 (s, 1H), 6.67 (s, 1H), 6.19 (s, 2H), 4.79-4.43 (m, 1H), 3.32 (s, 3H), 2.05 (s, 3H), 1.27 (d, J = 5.9 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 486. Q3

N-(5-(2,3-dihydro- [1,4]dioxino[2,3-b]pyridin- 6-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, 1H), 10.49 (s, 1H), 9.13 (s, 1H), 8.64 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.54-7.38 (m, 2H), 6.96 (s, 1H), 4.55- 4.52 (m, 2H), 4.38-4.35 (m, 2H), 3.43 (s, 3H), 2.42 (s, 3H), 2.11 (s, 3H). MS (ESI) m/e [M + 1]⁺ 456. Q4

N-(5-(3,4-dihydro-2H- pyrido[4,3-b][1,4]oxazin-7- yl)-4-((4-isopropoxy-6- (methylsulfonyl)pyridin- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.31 (s, 1H), 10.41 (s, 1H), 9.03 (s, 1H), 8.53 (s, 1H), 7.51 (s, 1H), 7.12-7.04 (m, 3H), 6.94 (s, 1H), 5.06-4.79 (m, 1H), 4.19 (s, 2H), 3.53 (s, 2H), 3.41 (s, 3H), 2.09 (s, 3H), 1.34 (d, J = 5.9 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 499. Q5

N-(5-(imidazo[1,2- b]pyridazin-6-yl)-4-((4- isopropoxy-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.61 (s, 1H), 9.81 (s, 1H), 8.97 (s, 1H), 8.50 (s, 1H), 8.44 (s, 1H), 8.18 (d, J = 12.0 Hz, 1H), 7.82 (s, 1H), 7.54 (d, J = 12.0 Hz, 1H), 7.02-7.01 (m, 1H), 6.82-6.81 (m, 1H), 4.77- 4.76 (m, 1H), 3.35 (s, 3H), 2.12 (s, 3H), 1.31 (d, J = 4.0 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 482. Q6

N-(5-(6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazin- 2-yl)-4-((4-isopropoxy-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.21 (s, 1H), 10.42 (s, 1H), 9.16 (s, 1H), 8.59 (s, 1H), 7.09 (d, J = 1.6 Hz, 1H), 6.77 (s, 1H), 6.73 (s, 1H), 4.89 (s, 3H), 4.32 (s, 2H), 4.16-4.12 (m, 2H), 3.46 (s, 3H), 2.11 (s, 3H), 1.34 (d, J = 5.9 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 487. Q7

N-(5-(4-actyl-3,4-dihydro- 2H-pyrido[3,2- b][1,4]oxazin-6-yl)-4-((4- isopropoxy-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, CDCl₃) δ 11.30 (s, 1H), 9.11 (s, 1H), 8.86 (s, 1H), 8.37 (s, 1H), 7.45-7.40 (m, 2H), 6.67 (s, 1H), 4.75- 4.71 (m, 1H), 4.40-4.35 (m, 2H), 4.15-4.10 (m, 2H), 3.38 (s, 3H), 2.56 (s, 3H), 2.23 (s, 3H), 1.39 (d, J = 6.0 Hz, 6H). MS (ESI) m/e [M + 1]⁺ 541. Q8

N-(5-(2,3-dihydro- [1,4]dioxino[2,3-c]pyridin- 7-yl)-4-((4-methoxy-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.51 (s, 1H), 10.46 (s, 1H), 9.10 (s, 1H), 8.63 (s, 1H), 8.38 (s, 1H), 7.61 (s, 1H), 7.09 (s, 1H), 6.84 (s, 1H), 4.43-4.39 (m, 4H), 3.95 (s, 3H), 3.43 (s, 3H), 2.11 (s, 3H). MS (ESI) m/e [M + 1]⁺ 472. Q9

N-(5-(benzo[b]thiophen-2- yl)-4-((4-methoxy-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (s, 1H), 8.92 (s, 1H), 8.60 (s, 1H), 8.14 (s, 1H), 8.10- 8.05 (m, 1H), 7.91 (s, 1H), 7.49- 7.46 (m, 1H), 7.42-7.38 (m, 1H), 7.35-7.33 (m, 1H), 7.02 (s, 1H), 6.71 (s, 1H), 3.77 (s, 3H), 3.35 (s, 3H), 2.12 (s, 3H). MS (ESI) m/e [M + 1]⁺ 469. Q10

N-(5-(6,7-dihydro-4H- thieno[3,2-c]pyran-2-yl)-4- ((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide 1H NMR (400 MHz, DMSO- d6) δ 10.49 (s, 1H), 8.97 (s, 1H), 8.73 (s, 1H), 8.23 (s, 1H), 7.36 (s, 1H), 7.14 (s, 1H), 7.05 (s, 1H), 4.65-4.60 (m, 2H), 3.95-3.90 (m, 2H), 3.28 (s, 3H), 2.85-2.80 (m, 2H), 2.36 (s, 3H), 2.08 (s, 3H). MS (ESI) m/e [M + 1]⁺ 459. Q11

N-(5-(2,3-dihydro- [1,4]dioxino[2,3-b]pyridin- 6-yl)-4-((4-methoxy-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 472. Q12

N-(5-(2,3-dihydro- [1,4]dioxino[2,3-c]pyridin- 7-yl)-4-((4-ethoxy-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 486. Q13

N-(5-(2,3-dihydro- [1,4]dioxino[2,3-c]pyridin- 7-yl)-4-((4-(2- methoxyethoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 516. Q14

N-(5-([1,3]dioxolo[4,5- b]pyridin-5-yl)-4-((4-(2- methoxyethoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 502. Q15

N-(5-([1,3]dioxolo[4,5- b]pyridin-5-yl)-4-((4- ethoxy-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 472. Q16

N-(5-([1,3]dioxolo[4,5- b]pyridin-5-yl)-4-((4- methoxy-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 458. Q17

N-(4-((4- (cyclopropylmethoxy)-6- (methylsulfonyl)pyridin-2- yl)amion)-5-(5-methyl- 4,5,6,7- tetrahydrothiazolo[5,4- c]pyridin-2-yl)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 529 Q18

N-(5-(2,3-dihydro- [1,4]dioxino[2,3-c]pyridin- 7-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide Molecular Weight: 455 Q19

N-(5-(2,3-dihydro- [1,4]dioxino[2,3-c]pyridin- 7-yl)-4-((4-(2- methoxyethoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide Molecular Weight: 516 Q20

N-(5-(6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazin- 2-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide Molecular Weight: 442 Q27

N-(4-((4-((1,4-dioxan-2- yl)methoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(3,3-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin- 6-yl)pyridin-2-yl)acetamide Molecular Weight: 586 Q28

N-(5-(3,3-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridine-6-yl)-4-((6- (methylsulfonyl)pyrazin-2- yl)amino)pyridine-2- yl)acetamide Molecular Weight: 471 Q29

N-(5-(3,3-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]yridine-6-yl)-4-((4-(2- hydroxypropan-2-yl)-6- (methylsulfonyl)pyridine- 2-yl)amino)pyridine-2- yl)acetamide Molecular Weight: 528 Q30

N-(5-(3,3-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridine-6-yl)-4-((5- fluoro-4-methyl-6- (methylsulfonyl)pyridine- 2-yl)amino)pyridine-2- yl)acetamide Molecular Weight: 502 Q39

N-(5-(3,3-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6- (methylsulfonyl)-4- morpholinopyridin-2- yl)amino)pyridin-2- yl)acetamide Molecular Weight: 555 Q41

(R)-N-(5-(3,3-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin- 6-yl)-4-((4-(3- methylmorpholino)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide Molecular Weight: 569 Q42

(S)-N-(5-(3,3-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(3- methylmorpholino)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide Molecular Weight: 569 Q44

(R)-N-(5-(3,3-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin- 6-yl)-4-((4-(1- methoxyethyl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide Molecular Weight: 528 Q45

(R)-N-(5-(2,2-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin- 6-yl)-4-((4-(3- methoxypyrrolidin-1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.41 (s, 1H), 10.40 (s, 1H), 8.77 (s, 1H), 8.50 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 6.71 (s, 1H), 6.15 (s, 1H), 4.18 (s, 2H), 4.05 (s, 1H), 3.47-3.34 (m, 4H), 3.26 (s, 3H), 3.22 (s, 3H), 2.03-2.01 (m, 5H), 1.29 (s, 6H). MS (ESI) m/e [M + H]⁺ = 569. Q47

N-(4-((4-(4- aminotetrahydro-2H-pyran- 4-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2,2-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin- 6-yl)pyridin-2-yl)acetamide Molecular Weight: 569 Q48

N-(4-((4-(4- (aminomethyl)tetrahydro- 2H-pyran-4-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2,2-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin- 6-yl)pyridin-2-yl)acetamide Molecular Weight: 583 Q56

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(3- hydroxy-3-methylazetidin- 1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyrid-in-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.58 (s, 1H), 10.51 (s, 1H), 8.84 (s, 1H), 8.57 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 6.63 (s, 1H), 6.04 (s, 1H), 5.78 (s, 1H), 4.25 (s, 2H), 3.95-3.90 (m, 2H), 3.86- 3.84 (m, 2H), 3.34 (s, 3H), 2.11 (s, 3H), 1.45 (s, 3H), 1.36 (s, 6H). MS (ESI) m/e [M + 1]⁺ 555. Q57

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(3- hydroxy-3- methylpyrrolidin-1-yl)-6- (methyl sulfonyl)pyridin-2- yl)amino)pyridin-2-yl) acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.50 (s, 1H), 10.44 (s, 1H), 8.88 (s, 1H), 8.57 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 6.72 (s, 1H), 6.14 (s, 1H), 4.93 (s, 1H), 4.25 (s, 2H), 3.50-3.45 (m, 2H), 3.34 (s, 3H), 3.30-3.25 (m, 2H), 2.09 (s, 3H), 2.00-1.95 (m, 2H), 1.36 (s, 9H). MS (ESI) m/e [M + 1]⁺ 569. Q58

N-(6-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-5-((6- (methylsulfonyl)-4- (tetrahydro-2H-pyran-4- yl)pyridin-2- yl)amino)pyridazin-3- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.89 (s, 1H), 11.07 (s, 1H), 9.48 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.62-7.53 (m, 2H), 7.08 (s, 1H), 4.33 (s, 2H), 4.02- 3.96 (m, 2H), 3.55-3.44 (m, 5H), 3.05-3.00 (m, 1H), 2.18 (s, 3H), 1.86-1.82 (m, 2H), 1.70-1.65 (m, 2H), 1.40 (s, 6H). MS (ESI) m/e [M + 1]⁺ 555. Q59

(R)-N-(5-(2,2-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin- 6-yl)-4-((4-(3-(2- hydroxyethoxy)pyrrolidin- 1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl) acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.54 (s, 1H), 10.65 (s, 1H), 8.73 (s, 1H), 8.55 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H), 6.24 (s, 1H), 4.28-4.22 (m, 2H), 3.56-3.38 (m, 9H), 3.33 (s, 3H), 2.15-2.10 (m, 5H), 1.36 (s, 6H). MS (ESI) m/e [M + 1]⁺ 599. Q60

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6- (methylsulfonyl)-4-(1- (2,2,2- trifluoroethyl)piperidin-4- yl)pyridin-2- yl)amino)pyridin-2-yl) acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.76 (s, 1H), 10.50 (s, 1H), 9.05 (s, 1H), 8.61 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.46 (s, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.05 (s, 1H), 4.26 (s, 2H), 3.42 (s, 3H), 3.27-3.19 (m, 2H), 3.05-3.00 (m, 2H), 2.74-2.64 (m, 1H), 2.50-2.46 (m, 2H), 2.11 (s, 3H), 1.85-1.80 (m, 2H), 1.70-1.61 (m, 2H), 1.37 (s, 6H). MS (ESI) m/e [M + 1]⁺ 635. Q61

(S)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(3-(2- hydroxyethoxy)pyrrolidin- 1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 11.49 (s, 1H), 10.45 (s, 1H), 8.86 (s, 1H), 8.57 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 6.78 (s, 1H), 6.21 (s, 1H), 4.62-4.60 (m, 1H), 4.25-4.20 (m, 3H), 3.54-3.49 (m, 6H), 3.43-3.41 (m, 4H), 3.35-3.32 (m, 1H), 2.12-2.10 (m, 5H), 1.36 (s, 6H). MS (ESI) m/e [M + 1]⁺ 599. Q62

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4- methyl-6′- (methylsulfonyl)-[3,4′- bipyridin]-2′- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ 12.01 (s, 1H), 10.54 (s, 1H), 9.16 (s, 1H), 8.65 (s, 1H), 8.55 (d, J = 4.0 Hz, 1H), 8.52 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.46-7.40 (m, 2H), 7.17 (s, 1H), 4.20 (s, 2H), 3.50 (s, 3H), 2.34 (s, 3H), 2.13 (s, 3H), 1.33 (s, 6H). MS (ESI) m/e [M + 1]⁺ 561. Q64

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4- methyl-6-(methylsulfonyl)- 3-oxo-3,4-dihydropyrazin- 2-yl)amino)pyridin-2- yl)acetamide [M + 1]⁺ 501 Q65

(S)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(3- methoxypiperidin-1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.52 (s, 1H), 10.43 (s, 1H), 8.95 (s, 1H), 8.57 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 1.8 Hz, 1H), 6.48 (d, J = 1.8 Hz, 1H), 4.22 (s, 2H), 3.72 (d, J = 12.7 Hz, 1H), 3.66-3.50 (m, 1H), 3.36 (s, 3H), 3.33- 3.19 (m, 6H), 2.10 (s, 3H), 1.98-1.87 (m, 1H), 1.75- 1.73 (m, 1H), 1.55-1.43 (m, 2H), 1.36 (s, 6H). MS (ESI) m/e [M + 1]⁺ 583 Q66

(R)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(3- methoxypiperidin-1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.51 (s, 1H), 10.43 (s, 1H), 8.94 (s, 1H), 8.57 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 1.7 Hz, 1H), 6.48 (d, J = 1.7 Hz, 1H), 4.21 (s, 2H), 3.73 (d, J = 11.3 Hz, 1H), 3.58-3.52 (m, 1H), 3.36 (s, 3H), 3.32-3.19 (m, 5H), 2.09 (s, 3H), 1.96-1.89 (m, 1H), 1.76-1.74 (m, 1H), 1.63-1.42 (m, 2H), 1.35 (s, 6H). MS (ESI) m/e [M + 1]⁺ 583 Q67

(S)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(3- ethoxypiperidin-1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 597 Q68

(R)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(3- ethoxypiperidin-1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 597 Q69

(S)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6- (methylsulfonyl)-4-(3- (trifluoromethoxy)pyrrolidin- 1-yl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 623 Q70

(R)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6- (methylsulfonyl)-4-(3- (trifluoromethoxy)pyrrolidin- 1-yl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 623 Q71

(S)-1-(2-((2-acetamido-5- (2,2-dimethyl-2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-4-yl)amino)-6- (methylsulfonyl)pyridin-4- yl)pyrrolidine-2- carboxamide MS (ESI) m/e [M + 1]⁺ 582 Q72

(R)-1-(2-((2-acetamido-5- (2,2-dimethyl-2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-4-yl)amino)-6- (methylsulfonyl)pyridin-4- yl)pyrrolidine-2- carboxamide MS (ESI) m/e [M + 1]⁺ 582 Q73

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(3- (methoxymethyl)pyrrolidin- 1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.45 (s, 1H), 10.43 (s, 1H), 8.88 (s, 1H), 8.56 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 1.5 Hz, 1H), 6.17 (s, 1H), 4.24 (s, 2H), 3.56-3.42 (m, 2H), 3.42-3.35 (m, 3H), 3.31 (s, 3H), 3.28 (s, 3H), 3.15-3.11 (m, 1H), 2.61 (m, 1H), 2.13-2.06 (m, 4H), 1.78 (m, 1H), 1.36 (s, 6H). MS (ESI) m/e [M + 1]⁺ 583 Q73A

(S)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(3- (methoxymethyl)pyrrolidin- 1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 583 Q74

(R)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(3- (methoxymethyl)pyrrolidin- 1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 583 Q75

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6- (methylsulfonyl)-4- (tetrahydro-2H-pyran-3- yl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.88 (s, 1H), 10.50 (s, 1H), 9.03 (s, 1H), 8.62 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.10 (s, 1H), 4.26 (s, 2H), 3.90-3.83 (m, 2H), 3.56-3.38 (m, 5H), 2.98- 2.92 (m, 1H), 2.11 (s, 3H), 2.01-1.98 (m, 1H), 1.91- 1.56 (m, 3H), 1.37 (s, 6H). MS (ESI) m/e [M + 1]⁺ 554 Q75A

(S)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6- (methylsulfonyl)-4- (tetrahydro-2H-pyran-3- yl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 554 Q76

(R)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6- (methylsulfonyl)-4- (tetrahydro-2H-pyran-3- yl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 554 Q77

(S)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((5-(3- methoxypyrrolidin-1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 569 Q78

(R)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((5-(3- methoxypyrrolidin-1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ 569 Q79

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6- (methylsulfonyl)-5- (tetrahydro-2H-pyran-4- yl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.76 (s, 1H), 10.51 (s, 1H), 8.78 (s, 1H), 8.62 (s, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 4.23 (s, 2H), 3.97 (dd, J = 11.2, 3.1 Hz, 2H), 3.78-3.70 (m, 1H), 3.43-3.36 (m, 5H), 2.10 (s, 3H), 1.84-1.61 (m, 4H), 1.36 (s, 6H). MS (ESI) m/e [M + 1]⁺ 554 Q80

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(5- methylpyridazin-4-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ = 562. Q81

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(5- methoxypyridazin-4-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ = 578. Q82

N-(4-((4-(cis-3-cyano-4- hydroxypyrrolidin-1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2,2-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-2-yl)acetamide MS (ESI) m/e [M + 1]⁺ = 580. Q83

N-(4-((4-(trans-3-cyano-4- hydroxypyrrolidin-1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2,2-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-2-yl)acetamide MS (ESI) m/e [M + 1]⁺ = 580. Q84

N-(4-((4-(cis-3-cyano-4- methoxypyrrolidin-1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2,2-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-2-yl)acetamide MS (ESI) m/e [M + 1]⁺ = 594. Q85

N-(4-((4-(trans-3-cyano-4- methoxypyrrolidin-1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2,2-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-2-yl)acetamide MS (ESI) m/e [M + 1]⁺ = 594. Q86

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6- (methylsulfonyl)-4- (tetrahydrofuran-3- yl)pyridin-2- yl)amino)pyridin-2- yl)acetamde MS (ESI) m/e [M + 1]⁺ = 540. Q86A

(S)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6- (methylsulfonyl)-4- (tetrahydrofuran-3- yl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ = 540. Q87

(R)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6- (methylsulfonyl)-4- (tetrahydrofuran-3- yl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ = 540. Q88

(S)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(2- (methoxymethyl)pyrrolidin- 1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ = 583. Q89

(R)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(2- (methoxymethyl)pyrrolidin- 1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ = 583. Q90

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6- (methylsulfonyl)-3- (tetrahydro-2H-pyran-4- yl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ = 554. Q91

(S)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((3-(3- methoxypyrrolidin-1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1] = 569. Q92

(R)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((3-(3- methoxypyrrolidin-1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + 1]⁺ = 569. Q93

cis-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-((cis-4- hydroxycyclohexyl)oxy)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 584 Q94

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-((trans- 4-hydroxycyclohexyl)oxy)- 6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 584 Q95

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-((cis-4- methoxycyclohexyl)oxy)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 598 Q96

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-((trans- 4-methoxycyclohexyl)oxy)- 6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 598 Q97

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6- (methylsulfonyl)-4-(5- azaspiro[2.4]heptan-5- yl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 565 Q98

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-((3- methyloxetan-3- yl)methoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.66 (s, 1H), 10.50 (s, 1H), 9.00 (s, 1H), 8.60 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 6.72 (s, 1H), 4.52 (s, 2H), 4.32 (s, 2H), 4.26 (s, 4H), 3.42 (s, 3H), 2.11 (s, 3H), 1.38-1.36 (m, 9H). MS (ESI) m/e [M + 1]⁺ 570. Q99

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(3,5- dimethylisoxazol-4-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 565 Q100

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-((2,4- dioxothiazolidin-3- yl)methyl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 599 Q101

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4- methoxy-6′- (methylsulfonyl)-[3,4′- bipyridin]-2′- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 577 Q102

(R)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(3- methylpyrrolidin-1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 553 Q103

(S)-N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(3- methylpyrrolidin-1-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 553 Q104

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6- (methylsulfonyl)-4- (pyrrolidin-1-yl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 539 Q105

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(2- hydroxypropan-2-yl)-6′- (methylsulfonyl)-[3,4′- bipyridin]-2′- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 605 Q106

N-(4-((4-(3- azabicyclo[3.1.0]hexan-3- yl)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2,2-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-2-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.52 (s, 1H), 10.43 (s, 1H), 8.88 (s, 1H), 8.57 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 1.6 Hz, 1H), 6.16 (d, J = 1.6 Hz, 1H), 4.26 (s, 2H), 3.54 (d, J = 9.9 Hz, 2H), 3.44 (d, J = 9.3 Hz, 2H), 3.33 (s, 3H), 2.10 (s, 3H), 1.76-1.74 (m, 2H), 1.36 (s, 6H), 0.83- 0.78 (m, 1H), 0.21-0.19 (m, 1H). MS (ESI) m/e [M + H]⁺ = 551. Q107

(S)-N-(4-((4-(3- (cyanomethoxy)pyrrolidin-1- yl)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2,2-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-2-yl)acetamide MS (ESI) m/e [M + H]⁺ = 594 Q108

N-(4-((6-cyano-6′- (methylsulfonyl)-[3,4′- bipyridin]-2′-yl)amino)-5- (2,2-dimethyl-2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-2-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.88 (s, 1H), 10.63 (s, 1H), 9.28 (d, J = 1.7 Hz, 1H), 9.12 (s, 1H), 8.70 (s, 1H), 8.61-8.59 (m, 1H), 8.31 (d, J = 8.2 Hz, 1H), 7.95 (s, 1H), 7.65-7.64 (m, 2H), 7.50 (d, J = 8.3 Hz, 1H), 4.29 (s, 2H), 3.54 (s, 3H), 2.19 (s, 3H), 1.42 (s, 6H). MS (ESI) m/e [M + H]⁺ = 572. Q109

N-(4-((2-cyano-6′- (methylsulfonyl)-[3,4′- bipyridin]-2′-yl)amino)-5- (2,2-dimethyl-2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-2-yl)acetamide MS (ESI) m/e [M + H]⁺ = 572 Q110

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(3- methylpyrazin-2-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.21 (s, 1H), 10.55 (s, 1H), 9.20 (s, 1H), 8.67 (d, J = 3.6 Hz, 3H), 7.81 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 4.23 (s, 2H), 3.52 (s, 3H), 2.69 (s, 3H), 2.13 (s, 3H), 1.35 (s, 6H). MS (ESI) m/e [M + H]⁺ = 562. Q111

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6- (methylsulfonyl)-4-(2,2,6,6- tetramethyltetrahydro-2H- pyran-4-yl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.80 (s, 1H), 10.51 (s, 1H), 9.03 (s, 1H), 8.61 (s, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.51 (s, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.11 (s, 1H), 4.25 (s, 2H), 3.43 (s, 3H), 3.34-3.33 (m, 1H), 2.11 (s, 3H), 1.78 (d, J = 12.7 Hz, 2H), 1.41-1.39 (m, 2H), 1.37 (s, 6H), 1.31 (s, 6H), 1.17 (s, 6H). MS (ESI) m/e [M + H]⁺ = 610. Q112

(R)-N-(4-((4-(2,2- dichlorocyclopropyl)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2,2-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-2-yl)acetamide MS (ESI) m/e [M + H]⁺ = 578 Q113

(S)-N-(4-((4-(2,2- dichlorocyclopropyl)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2,2-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-2-yl)acetamide MS (ESI) m/e [M + H]⁺ = 578 Q114

N-(4-((4-(5-cyanopyridazin- 4-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2,2-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-2-yl)acetamide MS (ESI) m/e [M + H]⁺ = 573 Q115

N-(4-((4-cyano-6′- (methyslulfonyl)-[3,4′- bipyridin]-2′-yl)amino)-5- (2,2-dimethyl-2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-2-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.01 (s, 1H), 10.57 (s, 1H), 9.13 (s, 1H), 9.06 (s, 1H), 8.96 (d, J = 4 Hz, 1H), 8.65 (s, 1H), 8.09 (d, J = 8 Hz, 1H), 7.83 (s, 1H), 7.60 (d, J = 8 Hz, 1H), 7.48-7.38 (m, 2H), 4.20 (s, 2H), 3.50 (s, 3H), 2.13 (s, 3H), 1.34 (s, 6H). MS (ESI) m/e [M + H]⁺ = 572 Q116

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(5- fluoropyridazin-4-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 566 Q117

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-fluoro- 6′-(methylsulfonyl)-[3,4′- bipyridin]-2′- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 565 Q118

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6′- (methylsulfonyl)-[2,4′- bipyridin]-2′- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 547 Q119

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6- (methylsulfonyl)-4-(thiazol- 4-yl)pyridin-2- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 11.93 (s, 1H), 10.52 (s, 1H), 9.32 (d, J = 1.7 Hz, 1H), 9.11 (s, 1H), 8.73 (d, J = 1.7 Hz, 1H), 8.64 (s, 1H), 8.06 (s, 1H), 7.78 (s, 1H), 7.60 (d, J = 8 Hz, 1H), 7.44 (d, J = 8 Hz, 1H), 4.27 (s, 2H), 3.48 (s, 3H), 2.12 (s, 3H), 1.37 (s, 6H). MS (ESI) m/e [M + H]⁺ = 553 Q120

N-(4-((4-(1- cyanocyclopropyl)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2,2-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-2-yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) 11.84 (s, 1H), 10.54 (s, 1H), 8.99 (s, 1H), 8.61 (s, 1H), 7.56 (d, J = 8 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 4.0 Hz, 1H), 7.14 (d, J = 4.0 Hz, 1H), 4.23 (s, 2H), 3.43 (s, 3H), 2.11 (s, 3H), 2.03-1.93 (m, 2H), 1.79-1.96 (m, 2H), 1.36 (s, 6H). MS (ESI) m/e [M + H]⁺ = 535 Q121

N-(4-((4-((3R)-3-cyano-2- azabicyclo[3.1.0]hexan-2- yl)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2,2-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-2-yl)acetamide MS (ESI) m/e [M + H]⁺ = 576 Q122

N-(4-((4-((3S)-3-cyano-2- azabicyclo[3.1.0]hexan-2- yl)-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2,2-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-2-yl)acetamide MS (ESI) m/e [M + H]⁺ = 576 Q123

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(2- methyl-2- morpholinopropoxy)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 627 Q124

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(2- methoxy-2-methylpropoxy)- 6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2- y)acetamide MS (ESI) m/e [M + H]⁺ = 572 Q125

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(2- hydroxy-2-methylpropoxy)- 6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 558 Q126

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(3,3- dimethylmorpholino)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide 1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 10.46 (s, 1H), 9.07 (s, 1H), 8.63 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 1.7 Hz, 1H), 6.68 (d, J = 1.8 Hz, 1H), 4.24 (s, 2H), 3.78-3.77 (m, 2H), 3.42-3.41 (m, 5H), 3.36-3.35 (m, 2H), 2.10 (s, 3H), 1.36 (s, 6H), 1.30 (s, 6H). MS (ESI) m/e [M + H]+ = 583. Q127

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4- isopropyl-6′- (methylsulfonyl)-[3,4′- bipyridin]-2′- yl)amino)pyridin-2- yl)acetamide ¹H NMR (400 MHz, DMSO- d₆) δ 12.24 (s, 1H), 10.55 (s, 1H), 9.21 (s, 1H), 8.68 (s, 1H), 8.63 (d, J = 4 Hz, 1H), 8.47 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 4 Hz, 1H), 7.53-7.36 (m, 2H), 7.11 (s, 1H), 4.18 (s, 2H), 3.53 (s, 3H), 3.01-2.96 (m, 1H), 2.13 (s, 3H), 1.33 (s, 6H), 1.21 (d, J = 8 Hz, 6H). MS (ESI) m/e [M + H]⁺ = 589 Q128

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(1- hydroxyethyl)-6′- (methylsulfonyl)-[3,4′- bipyridin]-2′- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 591 Q129

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((4-(1- methoxyethyl)-6′- (methylsulfonyl)-[3,4′- bipyridin]-2′- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 605 Q130

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6- (methylsulfonyl)- [1,3]dioxolo[4,5-c]pyridin-4- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 514 Q131

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((7- (methylsulfonyl)-2,3- dihydro-[1,4]dioxino[2,3- c]pyridin-5- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 528 Q132

N-(5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxino[2,3- b]pyridin-6-yl)-4-((6- (methylsulfonyl)-4- (trifluoromethyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 538 Q133

N-(4-((4-(difluoromethoxy)- 6-(methylsulfonyl)pyridin-2- yl)amino)-5-(2,2-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-2-yl)acetamide MS (ESI) m/e [M + H]⁺ = 536 Q134

N-(4-((4-cyclobutoxy-6- (methylsulfonyl)pyridin-2- yl)amino)-5-(2,2-dimethyl- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)pyridin-2-yl)acetamide MS (ESI) m/e [M + H]⁺ = 540 Q135

N-(5-(2,2-bis(methyl-d3)- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)-4-((6-(methylsulfonyl)-4- (tetrahydro-2H-pyran-4- yl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]+ = 560 Q136

N-(5-(2,2-bis(methyl-d3)- 2,3-dihydro- [1,4]dioxino[2,3-b]pyridin-6- yl)-4-((4-(methoxy-d3)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]+ = 509.

Example R1: Synthesis of N-(5-(4,4-dimethyl-4,5-dihydrothiazol-2-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide Step 1: Synthesis of methyl 6-chloro-4-(4-methoxybenzyl)amino)nicotinate

To a solution of methyl 4,6-dichloronicotinate (2 g, 9.7 mmol) and PMBNH₂ (2.1 g, 15.3 mmol) in DMF (20 mL) was added TEA (3 g, 29.7 mmol) at rt. The mixture was stirred at rt for 3 h. Then H₂O was added and the mixture was extracted with EA. The organic layer was concentrated and the crude product was used in the next step without purification. MS (ESI) m/e [M+H]⁺=307.

Step 2: Synthesis of 6-chloro-4-((4-methoxybenzyl)amino)nicotinic acid

A solution of 6-chloro-4-((4-methoxybenzyl)amino)nicotinate (3.43 g, 11.2 mmol) in THF (100 mL) was added LiOH·H₂O (1.5 g, 35.7 mmol) in H₂O (50 mL). The mixture was stirred at rt for overnight. The mixture was concentrated, and the aqueous layer was acidified by HCl (1N). The white solid was collected by filtration and the filter cake was washed with H₂O, then dried to give the desired product (2.56 g, yield 90% for two steps). MS (ESI) m/e [M+H]⁺=293.

Step 3: Synthesis of 6-chloro-N-(1-hydroxy-2-methylpropan-2-yl)-4-((4-methoxybenzyl)amino)nicotinamide

To a solution of 6-chloro-4-((4-methoxybenzyl)amino)nicotinic acid (300 mg, 1 mmol), 2-amino-2-methylpropan-1-ol (115.7 mg, 1.3 mmol), HOBT (148.5 mg, 1.1 mmol) and EDCI (383 mg, 2 mmol) in DMF (5 mL) was added DIEA (322.5 mg, 2.5 mmol) in one portion at rt. The mixture was stirred at rt for 5 h. Then the reaction was quenched with H₂O and extracted with EA. The organic layer was concentrated. The crude product was purified on Prep-TLC (PE:EA=1:1) to give the desired product (90 mg, yield 24.7%) as a colorless oil. MS (ESI) m/e [M+H]⁺=364.

Step 3: Synthesis of 6-acetamido-N-(1-hydroxy-2-methylpropan-2-yl)-4-((4-methoxybenzyl)amino)nicotinamide

A slurry of 6-chloro-N-(1-hydroxy-2-methylpropan-2-yl)-4-((4-methoxybenzyl)amino)nicotinamide (90 mg, 0.25 mmol), acetamide (73.8 mg, 1.25 mmol), Pd₂(dba)₃ (22.9 mg, 0.025 mmol), Xantphos (28.9 mg, 0.05 mmol) and Cs₂CO₃ (163 mg, 0.05 mmol) in 1,4-dioxane (5 mL) was stirred at 120° C. under N₂ for 5 h. The mixture was cooled to rt and filtered through celite. The filtrate was concentrated under vacuum and the crude product was purified by Prep-TLC (DCM:MeOH=15:1) to give the desired product as a colorless oil (230 mg, crude). MS (ESI) m/e [M+H]⁺=387.

Step 4: Synthesis of N-(5-(4,4-dimethyl-4,5-dihydrothiazol-2-yl)-4-((4-methoxybenzyl)amino)pyridin-2-yl)acetamide

A solution of 6-acetamido-N-(1-hydroxy-2-methylpropan-2-yl)-4-((4-methoxybenzyl)amino)nicotinamide (230 mg, 0.6 mmol), Lawesson reagent (720 mg, 1.8 mmol) in dioxane (8 mL) was irritated at 100° C. under microwave for 1 h. The mixture was cooled to rt and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=15:1) to give the desired product as a yellow solid (80 mg, yield 83% for two steps). MS (ESI) m/e [M+H]⁺=385.

Step 5: Synthesis of N-(4-amino-5-(4,4-dimethyl-4,5-dihydrothiazol-2-yl)pyridin-2-yl)acetamide

A solution of N-(5-(4,4-dimethyl-4,5-dihydrothiazol-2-yl)-4-((4-methoxybenzyl)amino)pyridin-2-yl)acetamide (80 mg, 0.21 mmol) in TFA (5 mL) was stirred at 50° C. for 16 h and 70° C. for 5 h. The mixture was cooled to rt and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification. MS (ESI) m/e [M+H]⁺=265.

Step 6: Synthesis of N-(5-(4,4-dimethyl-4,5-dihydrothiazol-2-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide

A solution of N-(4-amino-5-(4,4-dimethyl-4,5-dihydrothiazol-2-yl)pyridin-2-yl)acetamide (70 mg, 0.26 mmol), 2-bromo-6-(methylsulfonyl)pyridine (94 mg, 0.4 mmol), Pd₂(dba)₃ (24.7 mg, 0.027 mmol), Xantphos (31 mg, 0.053 mmol) and Cs₂CO₃ (173 mg, 0.53 mmol) in dioxane (5 mL) was stirred at 120° C. under N₂ for 7 h. The mixture was cooled to rt and filtered through celite. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=15:1) to give the desired product (3.19 mg, yield 3.62% for two steps) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.75 (s, TH), 10.63 (s, 1H), 9.27 (s, 1H), 8.32 (s, JH), 7.98 (t, J=7.9 Hz, TH), 7.56 (d, J=7.4 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 3.44 (s, 3H), 3.22 (s, 2H), 2.06 (s, 3H), 1.44 (s, 6H). MS (ESI) m/e [M+H]⁺=420.

The following Examples were prepared in a similar manner to the product Example R1:

R2

N-(5-(4,4-dimethyl-4,5- dihydrothiazol-2-yl)-4-((6- (methylsulfonyl)-4- (tetrahydro-2H-pyran-4- yl)pyridin-2- yl)amino)pyridin-2- yl)acetamide MS (ESI) m/e [M + H]⁺ = 504

Furtherly, all the following compounds can be obtained by similar methods of preparing the example compounds disclosed in the present disclosure.

Molecular # Compound Chemical Name Weight 1.

N-(4-((4-isopropoxy-6- (methylsulfonyl)pyridin-2-yl)amino)- 5-(1-methyl-1,3a,4,6,7,7a- hexahydropyrano[4,3-c]pyrazol-3- yl)pyridin-2-yl)acetamide Molecular Weight: 502 2.

N-(5-(6,7-dihydro-4H-pyrano[4,3- d]thiazol-2-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 459 3.

N-(4-((4-isopropoxy-6- (methylsulfonyl)pyridin-2-yl)amino)- 5-(5-methyl-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2- yl)pyridin-2-yl)acetamide Molecular Weight: 499 4.

N-(5-([1,3]dioxolo[4,5-c]pyridin-6- yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-y1)acetamide Molecular Weight: 441 5.

N-(5-([1,3]dioxolo[4,5-c]pyridin-4- yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 441 6.

N-(5-(benzo[d][1,3]dioxol-4-yl)-4- ((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 440 7.

N-(5-(5-methyl-4,5,6,7- tetrahydrothiazolo[5,4-c]pyridin-2- y1)-4-((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 472 8.

N-(5-(imidazo[1,2-a]pyrimidin-2-yl)- 4-((4-methyl-6- (methylsulfonyl)pyridin-2- y1)amino)pyridin-2-yl)acetamide Molecular Weight: 437 9.

N-(5-(1-methyl-1,4- dihydrochromeno[4,3-c]pyrazol-6- yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 504 10.

N-(5-(imidazo[2′,l′:2,3]thiazolo[5,4- b]pyridin-7-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 493 11.

N-(5-(1-methyl-1,4- dihydropyrazolo[3′,4′:4,5]pyrano[2,3- b]pyridin-7-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2- y1)amino)pyridin-2-yl)acetamide Molecular Weight: 505 12.

N-(4′-((4,4-dioxido-2,3-dihydro- [1,4]oxathiino[3,2-b]pyridin-6- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide Molecular Weight: 411 13.

N-(4-((4,4-dioxido-2,3-dihydro- [1,4]oxathiino[3,2-b]pyridin-6- yl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide Molecular Weight: 414 14.

N-(5-(imidazo[1,2-b]pyridazin-6-yl)- 4-((4-methyl-6- (methylsulfonyl)pyridin-2- y1)amino)pyridin-2-yl)acetamide Molecular Weight: 437 15.

N-(5-(1-methyl-1H-pyrazol-3-yl)-4- ((7-(methylsulfonyl)-3,4-dihydro-2H- pyrano[3,2-c]pyridin-5- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 442 16.

N-(4-((5,5-dioxido-3,4-dihydro-2H- [1,4]oxathiepino[3,2-b]pyridin-7- yl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide Molecular Weight: 428 17.

N-(4-((4-(2-hydroxypropan-2-yl)-6- (methylsulfonyl)pyridin-2-yl)amino)- 5-(1-methyl-1H-pyrazol-3-yl)pyridin- 2-yl)acetamide Molecular Weight: 444 18.

N-(5-(1-methyl-1H-pyrazol-3-yl)-4- ((6-(methylsulfonyl)-4- (tetrahydrofuran-3-yl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 456 19.

N-(4-((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide Molecular Weight: 486 20.

N-(4-((4-(1-hydroxycyclopropyl)-6- (methylsulfonyl)pyridin-2-yl)amino)- 5-(1-methyl-1H-pyrazol-3-yl)pyridin- 2-yl)acetamide Molecular Weight: 442 21.

N-(4-((4-(2-hydroxy-2- methylpropoxy)-6- (methylsulfonyl)pyridin-2-yl)amino)- 5-(1-methyl-1H-pyrazol-3-yl)pyridin- 2-yl)acetamide Molecular Weight: 474 22.

N-(4-((4-(3-hydroxy-2,2- dimethylpropoxy)-6- (methylsulfonyl)pyridin-2-yl)amino)- 5-(1-methyl-1H-pyrazol-3-yl)pyridin- 2-yl)acetamide Molecular Weight: 488 23.

N-(5-(imidazo[1,5-b]pyridazin-2-y1)- 4-((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 437 24.

N-(4-((4-(3-hydroxytetrahydrofuran- 3-y1)-6-(methylsulfonyl)pyridin-2- yl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide Molecular Weight: 472 25.

N-(5-(1-methyl-1H-pyrazol-3-yl)-4- ((4-(1-methyl-1H-pyrazol-3-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 466 26.

N-(4-((4-((1- hydroxycyclopropyl)methoxy)-6- (methylsulfonyl)pyridin-2-yl)amino)- 5-(1-methyl-1H-pyrazol-3-yl)pyridin- 2-y1)acetamide Molecular Weight: 472 27.

N-(4-((4-((1- methoxycyclopropyl)methoxy)-6- (methylsulfonyl)pyridin-2-yl)amino)- 5-(1-methyl-1H-pyrazol-3-y1)pyridin- 2-yl)acetamide Molecular Weight: 486 28.

N-(5-(1-methyl-1H-pyrazol-3-yl)-4- ((6-(methylsulfonyl)-4- morpholinopyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 471 29.

N-(5-(benzo[d]thiazol-2-y1)-4-((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 540 30.

N-(4-((1,1-dioxido-3,4-dihydro-2H- thiopyrano[2,3-b]pyridin-7- yl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide Molecular Weight: 412 31.

N-(5-(1-methyl-1H-pyrazol-3-yl)-4- ((7-(methylsulfonyl)-3,4-dihydro-2H- pyrano[3,2-c]pyridin-5- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 442 32.

N-(5-(1-methyl-1H-pyrazol-3-yl)-4- ((6-(methylsulfonyl)- [1,3]dioxolo[4,5-c]pyridin-4- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 430 33.

N-(5-(1-methyl-1H-pyrazol-3-yl)-4- ((6-(methylsulfonyl)imidazo[1,2- a]pyrazin-8-yl)amino)pyridin-2- yl)acetamide Molecular Weight: 423 34.

N-(5-(1-methyl-1H-pyrazol-3-yl)-4- ((5-(methylsulfonyl)-3,4-dihydro-2H- pyrano[3,2-c]pyridin-7- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 442 35.

N-(5-(2,6-dimethylmorpholino)-4′- ((4-(2-hydroxypropan-2-yl)-6- (methylsulfonyl)pyridin-2-yl)amino)- [2,3′-bipyridin]-6′-yl)acetamide Molecular Weight: 554 36.

N-(5-(2,6-dimethylmorpholino)-4′- ((6-(methylsulfonyl)-4- (tetrahydrofuran-3-yl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide Molecular Weight: 566 37.

N-(5-(2,6-dimethylmorpholino)-4′- ((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide Molecular Weight: 596 38.

N-(5-(2,6-dimethylmorpholino)-4′- ((4-(1-hydroxycyclopropyl)-6- (methylsulfonyl)pyridin-2-yl)amino)- [2,3′-bipyridin]-6′-yl)acetamide Molecular Weight: 552 39.

N-(5-(2,6-dimethylmorpholino)-4′- ((4-(2-hydroxy-2-methylpropoxy)-6- (methylsulfonyl)pyridin-2-yl)amino)- [2,3′-bipyridin]-6′-yl)acetamide Molecular Weight: 584 40.

N-(5-(2,6-dimethylmorpholino)-4′- ((4-(3-hydroxy-2,2- dimethylpropoxy)-6- (methylsulfonyl)pyridin-2-yl)amino)- [2,3′-bipyridin]-6′-yl)acetamide Molecular Weight: 598 41.

N-(5-(2,6-dimethylmorpholino)-4′- ((4-(3-methoxytetrahydrofuran-3-yl)- 6-(methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide Molecular Weight: 596.70 42.

N-(5-(2,6-dimethylmorpholino)-4′- ((4-(3-hydroxytetrahydrofuran-3-yl)- 6-(methylsulfonyl)pyridin-2- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide Molecular Weight: 582 43.

N-(5-(2,6-dimethylmorpholino)-4′- ((4-(1-methyl-1H-pyrazol-3-yl)-6- (methylsulfonyl)pyridin-2-yl)amino)- [2,3′-bipyridin]-6′-yl)acetamide Molecular Weight: 576 44.

N-(5-(2,6-dimethylmorpholino)-4′- ((4-((1- hydroxycyclopropyl)methoxy)-6- (methylsulfonyl)pyridin-2-yl)amino)- [2,3′-bipyridin]-6′-yl)acetamide Molecular Weight: 582 45.

N-(5-(2,6-dimethylmorpholino)-4′- ((4-((1- methoxycyclopropyl)methoxy)-6- (methylsulfonyl)pyridin-2-yl)amino)- [2,3′-bipyridin]-6′-yl)acetamide Molecular Weight: 596 46.

N-(5-(2,6-dimethylmorpholino)-4′- ((6-(methylsulfonyl)-4- morpholinopyridin-2-yl)amino)-[2,3′- bipyridin]-6′-yl)acetamide Molecular Weight: 581 47.

N-(5-(2,6-dimethylmorpholino)-4′- ((5,5-dioxido-3,4-dihydro-2H- [1,4]oxathiepino[3,2-b]pyridin-7- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide Molecular Weight: 538 48.

N-(5-(2,6-dimethylmorpholino)-4′- ((1,1-dioxido-3,4-dihydro-2H- thiopyrano[2,3-b]pyridin-7- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide Molecular Weight: 522 49.

N-(5-(2,6-dimethylmorpholino)-4′- ((7-(methylsulfonyl)-3,4-dihydro-2H- pyrano[3,2-c]pyridin-5-yl)amino)- [2,3′-bipyridin]-6′-yl)acetamide Molecular Weight: 552 50.

N-(5-(2,6-dimethylmorpholino)-4′- ((6-(methylsulfonyl)- [1,3]dioxolo[4,5-c]pyridin-4- yl)amino)-[2,3′-bipyridin]-6′- yl)acetamide Molecular Weight: 540 51.

N-(5-(2,6-dimethylmorpholino)-4′- ((6-(methylsulfonyl)imidazo[1,2- a]pyrazin-8-yl)amino)-[2,3′- bipyridin]-6′-yl)acetamide Molecular Weight: 536 52.

N-(5-(2,6-dimethylmorpholino)-4′- ((5-(methylsulfonyl)-3,4-dihydro-2H- pyrano[3,2-c]pyridin-7-yl)amino)- [2,3′-bipyridin]-6′-y1)acetamide Molecular Weight: 552 53.

N-(5-(6,7-dihydro-4H-pyrano[4,3- d]thiazol-2-y1)-4-((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 545 54.

N-(5-(benzo[d][1,3]dioxol-4-yl)-4- ((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-y1)acetamide Molecular Weight: 526 55.

N-(5-(benzo[d]isoxazol-3-yl)-4-((4- (3-(hydroxymethyl)tetrahydrofuran- 3-yl)-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-y1)acetamide Molecular Weight: 523 56.

N-(5-(benzo[d]isothiazol-3-y1)-4-((4- (3-(hydroxymethyl)tetrahydrofuran- 3-yl)-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-y1)acetamide Molecular Weight: 539 57.

N-(5-(benzo[b]thiophen-2-yl)-4-((4- (3-(hydroxymethyl)tetrahydrofuran- 3-yl)-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 538 58.

N-(4-((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)-5-(imidazo[1,2- alpyrimidin-2-y1)pyridin-2- yl)acetamide Molecular Weight: 523 59.

N-(4-((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)-5-(1-methyl-1,4- dihydrochromeno[4,3-c]pyrazol-6- yl)pyridin-2-yl)acetamide Molecular Weight: 590 60.

N-(4-((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)-5- (imidazo[2′,l′:2,3]thiazolo[5,4- b]pyridin-7-y1)pyridin-2- yl)acetamide Molecular Weight: 579 61.

N-(4-((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)-5-(1-methyl-1,4- dihydropyrazolo[3′,4′:4,5]pyrano[2,3- b]pyridin-7-yl)pyridin-2- yl)acetamide Molecular Weight: 591 62.

N-(4-((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)-5-(6-oxo-1,6- dihydropyridazin-3-yl)pyridin-2- yl)acetamide Molecular Weight: 500 63.

N-(4-((4-(3- (hydroxymethyl)tetrahydrofuran-3- y1)-6-(methylsulfonyl)pyridin-2- yl)amino)-5-(6-oxopyridazin-1(6H)- yl)pyridin-2-yl)acetamide Molecular Weight: 500 64.

N-(5-(6-((2S,6R)-2,6- dimethylmorpholino)pyridazin-3-y1)- 4-((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 597 65.

N-(4-((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)-5-(3-oxo-8,9- dihydropyrano[4,3,2-de]phthalazin- 2(3H)-yl)pyridin-2-y1)acetamide Molecular Weight: 592 66.

N-(4-((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)-5-(7-methyl-3-oxo-8,9- dihydro-3H-pyrido[4,3,2- de]phthalazin-2(7H)-yl)pyridin-2- yl)acetamide Molecular Weight: 605 67.

N-(4′-((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)-5-(1-oxoisoindolin-2-yl)- [2,3′-bipyridin]-6′-yl)acetamide Molecular Weight: 614 68.

N-(5-(2,3-dihydropyrazolo[5,1- b]oxazol-6-yl)-4-((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-y1)acetamide Molecular Weight: 514 69.

N-(5-(2,2-dimethyl-2,3- dihydropyrazolo[5,1-b]oxazol-6-yl)- 4-((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 542 70.

N-(4-((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)-5-(5′H, 7′H- spiro[cyclopropane-1,6′- pyrazolo[5,1-b][1,3]oxazin]-2′- yl)pyridin-2-yl)acetamide Molecular Weight: 554 71.

N-(4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)- 5-(pyridin-2-yloxy)pyridin-2- yl)acetamide Molecular Weight: 413 72.

N-(5-(1H-imidazol-2-yl)-4-((4- methyl-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 386 73.

N-(5-(4-(2-hydroxypropan-2- yl)furan-2-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-y1)acetamide Molecular Weight: 444 74.

N-(5-(furan-2-yl)-4-((4-(3- methoxytetrahydrofuran-3-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 472 75.

N-(5-(1H-benzo[d]imidazol-2-y1)-4- ((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 436 76.

N-(3-fluoro-5-(2-hydroxypropan-2- y1)-4′-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)- [2,3′-bipyridin]-6′-yl)acetamide Molecular Weight: 473 77.

N-(3-fluoro-5-(2-hydroxypropan-2- yl)-4′-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)- [2,3′-bipyridin]-6′-yl)acetamide Molecular Weight: 473 78.

N-(5-(2-hydroxypropan-2-yl)-4- methyl-4′-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)- [2,3′-bipyridin]-6′-yl)acetamide Molecular Weight: 469 79.

N-(5-(2,6-dimethylmorpholino)-4′- ((6-(methylsulfonyl)-4- ((tetrahydrofuran-3- yl)methoxy)pyridin-2-yl)amino)- [2,3′-bipyridin]-6′-yl)acetamide Molecular Weight: 596 80.

N-(5-(2,6-dimethylmorpholino)-4′- ((6-(methylsulfonyl)-4- (((tetrahydrofuran-3- yl)oxy)methyl)pyridin-2-yl)amino)- [2,3′-bipyridin]-6′-yl)acetamide Molecular Weight: 596 81.

N-(5-(3-methoxy-1-methyl-1H- pyrazol-4-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 430 82.

N-(4-((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)-5-(3-methoxy-1-methyl- 1H-pyrazol-4-y1)pyridin-2- yl)acetamide Molecular Weight: 516 83.

N-(5-(6,7-dihydro-4H-furo[3,2- c]pyran-2-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 442 84.

N-(5-(5-methyl-4,5,6,7- tetrahydrofuro[3,2-c]pyridin-2-yl)-4- ((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 455 85.

N-(5-(cyclopropylmethoxy)-4-((4-(1- methyl-1H-pyrazol-3-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 456 86.

N-(5-((1- hydroxycyclopropyl)methoxy)-4-((4- (1-methyl-1H-pyrazol-3-yl)-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 472 87.

N-(5-(benzo[d]oxazol-2-yl)-4-((4-(3- (hydroxymethyl)tetrahydrofuran-3- yl)-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-y1)acetamide Molecular Weight: 524 88.

N-(5-(2,2-dimethyl-3-oxo-3,4- dihydro-2H-pyrido[3,2- b][1,4]oxazin-6-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 497 89.

N-(4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)- 5-(pyrazolo[1,5-a]pyrazin-2- yl)pyridin-2-yl)acetamide Molecular Weight: 437 90.

N-(4-((4-(2-methoxyethoxy)-6- (methylsulfonyl)pyridin-2-yl)amino)- 5-(pyrazolo[1,5-a]pyrazin-2- yl)pyridin-2-yl)acetamide Molecular Weight: 498 91.

N-(4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)- 5-(pyrazolo[1,5-c]pyrimidin-2- yl)pyridin-2-yl)acetamide Molecular Weight: 437 92.

N-(4-((4-(2-methoxyethoxy)-6- (methylsulfonyl)pyridin-2-yl)amino)- 5-(pyrazolo[1,5-c]pyrimidin-2- yl)pyridin-2-y1)acetamide Molecular Weight: 498 93.

N-(4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)- 5-(pyrazolo[1,5-a]pyrimidin-2- yl)pyridin-2-yl)acetamide Molecular Weight: 437 94.

N-(4-((4-(2-methoxyethoxy)-6- (methylsulfonyl)pyridin-2-yl)amino)- 5-(pyrazolo[1,5-a]pyrimidin-2- yl)pyridin-2-yl)acetamide Molecular Weight: 498 95.

N-(4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)- 5-(pyrazolo[1,5-a]pyrimidin-5- yl)pyridin-2-yl)acetamide Molecular Weight: 437 96.

N-(4-((4-(2-methoxyethoxy)-6- (methylsulfonyl)pyridin-2-yl)amino)- 5-(pyrazolo[1,5-a]pyrimidin-5- yl)pyridin-2-yl)acetamide Molecular Weight: 498 97.

N-(5-(2,2-dimethyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-6-yl)-4-((6- (methylsulfonyl)-4-(tetrahydro-2H- pyran-4-yl)pyridin-2- yl)amino)pyridin-2-yl)acetamide Molecular Weight: 553

Biochemical Assay and Cellular Assay Assay A: TYK2-JH2 Biochemical Assay

Compounds disclosed herein were tested for blocking of TYK2-JH2 (aa 575-869, in-house) protein with its probe in an assay based on Homogeneous Time Resolved Fluorescence. Compound dilution is done according to the following protocol: (1) Prepare 500× compounds solution in DMSO from 500 uM by 5-fold dilution, total 10 doses were included; (2) Prepare 10× compounds solution in an assay buffer containing 20 mM HEPES, pH 7.5, 10 mM MgCl2, 0.005% BSA, 2 mM DTT, 0.015% Brij-35 by transferring 1 μl serial 500× stock solution into 49 μl assay buffer. 4 d of 0.2 nM recombinant TYK2-JH2 protein was pre-incubated with 1 μl of 10× serial dilution of compounds at room temperature for 0.5 hour. Then 5 μl of 10 nM in-house Probe 1 (6-((3,5-dimethylphenyl)amino)-8-((4,26-dioxo-30-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)-7,10,13,16,19,22-hexaoxa-3,25-diazatriacontyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide, KD=10 nM), 5 μl Mab Anti-6His Tb cryptate Gold (Cat: 61HI2TLB, Cisbio Bioassays) and Streptavidin-XL665 (Cat: 610SAXLB, Cisobio Bioassays) mixture were added to plate and further incubated at room temperature for 1 hour. The HTRF signals (ex337 nm, em620 nm/665 nm) were read on BMG PHERAstar FS instrument. The inhibition percentage of TYK2 interaction with its probe in presence of increasing concentrations of compounds was calculated based on the ratio of fluorescence at 615 nm to that at 665 nm. The IC50 for each compound was derived from fitting the data to the four-parameter logistic equation by Dotmatics.

Assay B: JAK1-JH2 Biochemical Assay

Compounds disclosed herein were tested for blocking of JAK1-JH2 protein (aa 561-860, in-house) with its probe in an assay based on Homogeneous Time Resolved Fluorescence. Compound dilution is done according to the following protocol: (1) Prepare 500× compounds solution in DMSO from 500 uM by 5-fold dilution, total 10 doses were included; (2) Prepare 10× compounds solution in an assay buffer containing 20 mM HEPES, pH 7.5, 10 mM MgCl2, 0.005% BSA, 2 mM DTT, 0.015% Brij-35 by transferring 1 μl serial 500× stock solution into 49 μl assay buffer. 4 μL of 1.17 nM recombinant JAK1-JH2 protein was pre-incubated with 1 μl of 10× serial dilution of compounds at room temperature for 0.5 hour. Then 5 μL of 2.9 nM in-house Probe 2 (N-(2-(4-(2-(methyl(4-((((Z)-2-oxoindolin-3-ylidene)(phenyl)methyl)amino)phenyl)amino)-2-oxoethyl)piperazin-1-yl)ethyl)-1-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)-3,6,9,12,15,18-hexaoxahenicosan-21-amide, KD=2.9 nM), 5 μl Mab Anti-6His Tb cryptate Gold (Cat: 61HI2TLB, Cisbio Bioassays) and Streptavidin-XL665 (Cat: 610SAXLB, Cisobio Bioassays) mixture were added to plate and further incubated at room temperature for 1 hour. The HTRF signals (ex337 nm, em620 nm/665 nm) were read on BMG PHERAstar FS instrument. The inhibition percentage of JAK1 interaction with its probe in presence of increasing concentrations of compounds was calculated based on the ratio of fluorescence at 615 nm to that at 665 nm. The IC50 for each compound was derived from fitting the data to the four-parameter logistic equation by Dotmatics.

The probes herein used in assays can also be prepared according to the conventional synthesis methods well-known by a chemist.

Assay C: IL-12-JAK2, TYK2/p-STAT4 (Tyr693) Inhibition IC50 Cellular Assay

To evaluate the inhibition effect of compounds disclosed herein on JAK2, TYK2/p-STAT4 (Tyr693) activated by IL-12 in NK-92 cell line, NK-92 cells were collected and washed 3 times by DPBS and resuspended in MEM-α (GIBCO, Cat #12561056) with 10% FBS (Gibco, Cat #10099, Lot #1891605), without IL-2 (R&D systems, Cat #202-IL), starved overnight. Cells were collected and resuspended in 1640 medium (phenol red free, Gibco, Cat #11835-030) with 0.1% BSA, and 12.5 μl/5×10⁴/well cell suspension were seeded to the 96-well plate (Corning, Cat #3799). Then cells were treated with compounds diluted in 0.2% DMSO 1640 medium, at 37° C., 1 h. Dilution is done according to the following protocol: (1) make 500× compounds solution in DMSO from 5 mM by 4-fold dilution, total 8 doses were included; (3) make 2× compounds solution in assay medium by transferring 0.5 μl serial 500× stock solution into 125 μl assay medium; (4) 15 μl of 2× serial solution is added to cells and incubate at 37° C. for 1 h, the final compound conc. is 10000, 2500, 625, 156.25, 39, 9.8, 2.4 and 0.61 nM, respectively. After 1 h, cells were treated with 2.5 μl medium containing IL-12 at 37° C. (R&D systems, Cat #219-IL-005, final conc. 40 ng/ml), 30 min. Following cells were lysed with 7.5 μl lysis buffer at RT, shaking on shaker for 1 h. 10 μL of cell lysate were transferred to a PE 384-well Proxiplate detection plate, and 5 μL of pre-mixed Alphascreen beads were added to each well. Covered the plate with a plate sealer, span 1000 rpm for 1 min, mix, Incubated overnight at room temperature. Read on BMG PheraStar with Alphascreen protocol. IC 50 values were calculated by fitting dependent data to the four-parameter logistic model using dotmatics software. The assay was performed by using AlphaLISA SureFire Ultra p-STAT4 (Tyr693) Assay Kit—High Volume (PE, Cat #ALSU-PST4-A-HV).

Assay D: IL-6-JAK1/p-STAT3 (Tyr705) Inhibition IC50 Cellular Assay

To evaluate the inhibition effect of compounds disclosed herein on JAK1/p-STAT3 (Tyr705) activated by IL-6 in TF-1 cell line, TF-1 cells were collected and washed 3 times by DPBS and resuspended in RPMI-1640 (phenol red free, Gibco, Cat #11835-030) with 0.1% FBS (Gibco, Cat #10099, Lot #1891605), without GM-CSF (R&D systems, Cat #215-GM-050), starved overnight. Cells were collected and resuspended in 1640 medium (phenol red free, Gibco, Cat #11835-030) with 0.1% BSA, and 12.5 μl/10×10⁴/well cell suspension were seeded to the 96-well plate (Corning, Cat #3799). Then cells were treated with compounds diluted in 0.2% DMSO 1640 medium, at 37° C., 1 h. Dilution is done according to the following protocol: (1) make 500× compounds solution in DMSO from 5 mM by 4-fold dilution, total 8 doses were included; (3) make 2× compounds solution in assay medium by transferring 0.5 μl serial 500× stock solution into 1251 assay medium; (4) 15 μl of 2× solution is added to cells and incubate at 37° C. for 1 h, the final compound cone. is 10000, 2500, 625, 156.25, 39, 9.8, 2.4 and 0.61 nM, respectively. After 1 h, cells were treated with 2.5 μl medium containing IL-6 at 37° C. (R&D systems, Cat #206-LL-010, final conc. 50 ng/ml), 30 min. Following cells were lysed with 10 μl lysis buffer at RT, shaking on shaker for 1 h. 16 μL of cell lysate were transferred to a PE 384-well HTRF detection plate, and 4 μL of pre-mixed HTRF antibodies were added to each well. Covered the plate with a plate sealer, span 1000 rpm for 1 min, mix, Incubated overnight at room temperature. Read on BMG PheraStar with HTRF protocol (337 nm-665 nm-620 nm). IC 50 values were calculated by fitting dependent data to the four-parameter logistic model using dotmatics software. The assay was performed by using HTRF Phospho-STAT3 (Tyr705) Cellular Assay Kit (Cisbio, Cat #62AT3PEG).

Compounds disclosed herein showed picomolar to nanomolar bio-chemical activity in TYK2-JH2 binding assay and also showed nanomolar activity in cellular assay. In the meanwhile, these compounds showed excellent selectivity in TYK2 bio-chemical assay against JAK1 and in TYK2 cellular assay against JAK2. See the following Tables from 1 to 14.

TABLE 1 Biochemical assay Cellular assay Selec- Selec- TYK2- JAK1- tivity pSTAT4/ pSTAT5/ tivity JH2 JH2 fold IL-12 GM-CSF fold IC50 IC50 (TYK2/ IC50 IC50 (TYK2/ Example (nM) (nM) JAK1) (nM) (nM) JAK2) A1  0.052 15 288 79.5 >10000 >125 A2  5.2 828 159 — — — A3  0.035 — — 2.53 >10000 >3952 A4  0.52 59 113 — — — A5  0.49 59 120 — — — A6  0.14 18 128 51 >10000 >196 A7  670 >10000 14 — — — A8  0.26 — — — — — A9  0.041 — — 1.33 >10000 >7518 A10 2.4 — — 2996 — — A11 0.063 — — 41.7 >10000 >239 A12 0.037 — — 16.8 >10000 >595 A13 0.08 — — — — — A14 0.022 — — 0.969 >10000 >10319 A15 0.04 — — 0.687 3462 5039 A16 0.021 — — 0.667 >10000 >14992 A17 0.028 — — 1.64 >10000 >6097 A18 8.15 — — — — — A19 0.034 — — 1.53 >10000 >6535 A20 0.03 — — 1.12 2379 2124 A21 — — — — — — A22 — — — — — — A23 — — — — — — A24 0.027 — — 1.85 >10000 >5405 A25 0.027 — — 0.596 >10000 >16778 A26 0.032 — — 0.405 >10000 >24691 A27 0.034 — — 2.1 >10000 >4761 A28 0.033 — — 1.52 >10000 >6578 A29 0.042 — — 0.452 >10000 >22123 A30 — — — — — — A31 — — — — — —

TABLE 2 Biochemical assay Cellular assay Selec- Selec- TYK2- JAK1- tivity pSTAT4/ pSTAT5/ tivity JH2 JH2 fold IL-12 GM-CSF fold IC50 IC50 (TYK2/ IC50 IC50 (TYK2/ Example (nM) (nM) JAK1) (nM) (nM) JAK2) B1  0.038 7.4 194 9.89 >10000 >1011 B2  5.8 — — — — — B3  1.1 9 8.1 — — — B4  0.019 — — 2.53 >10000 >3952 B5  0.016 0.31 19 0.243 >10000 >41152 B6  0.018 1.2 666 1.21 >10000 >8264 B7  0.016 — — 5.58 >10000 >1792 B8  0.047 — — 1.68 >10000 >5952 B9  0.53 — — — — — B10 0.045 — — — — — B11 0.019 — — — — — B12 0.034 — — 0.74 610 824 B13 0.43 18 42 183 >10000 >54 B14 80 145 1 — — — B15 117 234 1 — — — B16 0.03 — — 0.513 4292 8366 B17 0.035 — — 2.05 >10000 >4878 B18 0.036 — — 1.05 >10000 >9523 B19 18 257 14.2 — — — B20 1.5 76 50 — — — B21 0.047 — — 0.443 2490 5620 B22 0.025 — — 12.61 2490 197 B23 0.04 — — 0.307 1001 3260 B24 — — — — — — B25 — — — — — —

TABLE 3 Biochemical assay Cellular assay Selec- Selec- TYK2- JAK1- tivity pSTAT4/ pSTAT5/ tivity JH2 JH2 fold IL-12 GM-CSF fold IC50 IC50 (TYK2/ IC50 IC50 (TYK2/ Example (nM) (nM) JAK1) (nM) (nM) JAK2) C1  0.027 — — 0.881 563 639 C2  0.026 — — 0.312 962 3083 C3  0.032 — — 5.81 >10000 >1721 C4  0.034 — — 4.35 >10000 >2298 C5  0.032 — — 21.9 >10000 >456 C6  0.054 — — 26.02 >10000 >381 C7  — — — — — — C8  — — — — — — C9  0.027 — — 0.672 >10000 >14880 C10 — — — — — — C11 — — — — — — C12 — — — — — — C13 — — — — — — C14 — — — — — — C15 — — — — — — C16 — — — — — — C17 0.022 — — 0.605 >10000 >16528 C18 0.023 — — 0.639 4873 7625 C19 0.023 — — — — — C20 0.023 — — — — — C21 0.024 — — 0.995 >10000 >10050 C22 0.023 — — 0.476 >10000 >21008 C23 0.022 — — 0.63 2600 4126 C24 — — — — — — C25 0.037 — — 0.827 1065 1288

TABLE 4 Biochemical assay Cellular assay Selec- Selec- TYK2- JAK1- tivity pSTAT4/ pSTAT5/ tivity JH2 JH2 fold IL-12 GM-CSF fold IC50 IC50 (TYK2/ IC50 IC50 (TYK2/ Example (nM) (nM) JAK1) (nM) (nM) JAK2) D1  0.047 — — 0.251 >10000 >39840 D2  0.038 — — 15.6 >10000 >641 D3  0.08 — — 4.8 >10000 >2083 D4  0.044 — — 0.262 >10000 >38167 D5  0.036 — — 0.99 >10000 >10101 D6  0.025 — — 0.593 >10000 >16863 D7  0.031 — — 0.805 >10000 >12422 D8  0.036 — — 0.443 >10000 >22573 D9  0.021 — — 0.479 >10000 >20876 D10 0.052 — — 12.67 >10000 >789 D11 — — — — — —

TABLE 5 Biochemical assay Cellular assay Selec- Selec- TYK2- JAK1- tivity pSTAT4/ pSTAT5/ tivity JH2 JH2 fold IL-12 GM-CSF fold IC50 IC50 (TYK2/ IC50 IC50 (TYK2/ Example (nM) (nM) JAK1) (nM) (nM) JAK2) E1 0.022 — — 4.55 >10000 >2197 E2 0.017 — — 0.325 5807 17867 E3 0.035 — — 0.645 >10000 >15503 E4 0.022 — — 0.536 >10000 >18656 E5 0.022 — — 0.501 >10000 >19960 E6 0.029 — — 2.72 >10000 >3676 E7 0.02 — — 0.447 >10000 >22371 E8 0.034 — — 2.86 >10000 >3496 E9 0.022 — — 0.504 >10000 >19960

TABLE 6 Biochemical assay Cellular assay Selec- Selec- TYK2- JAK1- tivity pSTAT4/ pSTAT5/ tivity JH2 JH2 fold IL-12 GM-CSF fold IC50 IC50 (TYK2/ IC50 IC50 (TYK2/ Example (nM) (nM) JAK1) (nM) (nM) JAK2) F1 0.046 — — 1.23 >10000 >8130 F2 0.051 — — 22.14 >10000 >451 F3 0.068 — — — — — F4 0.324 — — — — — F5 0.061 — — — — — F6 0.532 — — — — — F7 0.085 — — — — — F8 0.087 — — — — — F9 0.06 — — 5.45 >10000 > 1834 F10 0.04 — — — — — F11 0.037 — — 0.705 >10000 >14184 F12 0.034 — — 1.35 >10000 >7407 F13 0.21 — — — — — F14 0.13 — — — — — F15 0.073 — — — — — F16 0.027 — — — — — F17 0.054 — — 1.25 >10000 >8000 F18 0.052 — — — — — F19 0.036 — — 3.06 >10000 >3267 F20 0.031 — — 1.45 >10000 >6896 F21 0.026 — — 3.54 >10000 >2814 F22 0.026 — — 1.82 >10000 >5494 F23 0.020 — — 1.07 >10000 >9345 F24 0.033 — — 0.82 >10000 >12195 F25 0.029 — — 0.446 >10000 >22421

TABLE 7 Biochemical assay Cellular assay Selec- Selec- TYK2- JAK1- tivity pSTAT4/ pSTAT5/ tivity JH2 JH2 fold IL-12 GM-CSF fold IC50 IC50 (TYK2/ IC50 IC50 (TYK2/ Example (nM) (nM) JAK1) (nM) (nM) JAK2) G1 0.026 4.9 188 14.4 >10000 >694 G2 0.067 — — 14.2 >10000 >704 G3 0.05 — — 224 >10000 >44 G4 0.048 — — 16 >10000 >625

TABLE 8 Biochemical assay Cellular assay Selec- Selec- TYK2- JAK1- tivity pSTAT4/ pSTAT5/ tivity JH2 JH2 fold IL-12 GM-CSF fold IC50 IC50 (TYK2/ IC50 IC50 (TYK2/ Example (nM) (nM) JAK1) (nM) (nM) JAK2) H1  0.016 1.4 87.5 2.6 >10000 >3846 H2  0.036 — — 0.939 >10000 >10649 H3  0.048 — — 8.52 7185 >843 H4  0.047 — — — — — H5  0.015 — — 0.323 1675 5185 H6  0.014 — — 1.25 8872 7097 H7  0.046 — — 1.22 >10000 >8196 H8  0.041 — — 21.66 >10000 >461 H9  0.016 — — 0.503 1583 3147 H10 0.017 — — 16.45 >10000 607 H11 0.027 — — 1 >10000 >10000 H12 0.022 — — 5.1 >10000 >1960 H13 0.042 — — 0.676 4075 6028 H14 0.034 — — 0.727 >10000 >13755 H15 0.029 — — 4.89 >10000 >2044 H16 0.028 — — 7.51 >10000 >1331 H17 0.034 — — 67 >10000 >149 H18 0.032 — — 5.54 >10000 >1805 H19 0.028 — — 3.2 >10000 >3125 H20 0.046 — — 35.2 >10000 >284 H21 0.024 — — 2.24 >10000 >4464 H22 0.038 — — 2.76 >10000 >3623 H23 0.034 — — 5.7 >10000 >1754 H24 0.034 — — 5.39 >10000 >1855 H25 0.038 — — 7.53 >10000 >1328 H26 0.039 — — 11.7 >10000 >854 H27 0.031 — — 2.72 >10000 >3676 H28 0.03 — — 29.2 >10000 >342 H29 0.022 — — 1.77 8491 4797 H30 0.023 — — 0.972 >10000 >10288 H31 0.023 — — 0.935 >10000 >10695 H32 0.023 — — 0.447 >10000 >22371 H33 0.019 — — 0.777 >10000 >22371 H34 0.023 — — 1.12 >10000 >8928 H35 0.028 — — 3.17 >10000 >3154 H36 0.022 — — 1.95 >10000 >5128 H37 — — — — — — H38 — — — — — — H39 — — — — — — H40 — — — — — — H41 — — — — — — H42 — — — — — — H43 0.034 — — 5.39 >10000 >1855

TABLE 9 Biochemical assay Cellular assay Selec- Selec- TYK2- JAK1- tivity pSTAT4/ pSTAT5/ tivity JH2 JH2 fold IL-12 GM-CSF fold IC50 IC50 (TYK2/ IC50 IC50 (TYK2/ Example (nM) (nM) JAK1) (nM) (nM) JAK2) J2  0.022 — — 3 >10000 >3333 J3  0.026 — — 0.286 >10000 >34965 J4  0.028 — — 4.94 >10000 >2024 J5  0.022 — — 2.05 >10000 >4878 J6  0.033 — — 7.94 >10000 >1259 J7  0.19 — — 66.23 >10000 >150 J8  0.073 — — 7.67 >10000 >1303 J9  0.083 — — 6.54 >10000 >1529 J10 0.05 — — 6.34 >10000 >1577 J11 0.017 — — 0.275 6415 23327 J12 0.017 — — 0.847 >10000 >11806 J13 0.054 — — 1.18 >10000 >8474 J14 0.033 — — 0.792 >10000 >12626 J15 0.016 — — 5.9 >10000 >1694 J16 0.015 — — 2.52 >10000 >3968 J17 0.043 — — 6.8 >10000 >1470 J18 0.028 — — 0.399 >10000 >25062 J19 0.015 — — 0.882 >10000 >1137 J20 0.026 — — 3 >10000 >3333 J21 0.017 — — 0.72 >10000 >13888 J22 0.037 — — 1.93 >10000 >5181 J23 0.044 — — 0.862 1354 1570 J24 0.028 — — 6.05 >10000 >1652 J25 0.025 — — 2.91 >10000 >3436 J26 0.023 — — 5.5 >10000 >1818 J27 0.04 — — 0.439 >10000 >22779 J28 0.053 — — 3.14 >10000 >3184 J29 0.045 — — 12.41 >10000 >805 J30 0.054 — — 4.82 >10000 >2074 J31 0.076 — — 14.97 >10000 >668 J32 0.079 — — 8.79 >10000 >1137 J33 0.12 — — — — — J34 0.067 — — 9.69 >10000 >1031 J35 0.036 — — 8.13 >10000 >1230 J36 0.043 — — 5.05 >10000 >1980 J37 0.035 — — 19.1 >10000 >523 J38 0.024 — — 1.98 >10000 >5050 J39 0.036 — — 10.69 >10000 >935 J40 0.029 — — 0.326 >10000 >30674 J41 0.027 — — 2.98 >10000 >3355 J42 0.05 — — 0.796 >10000 >12562 J43 0.025 — — 0.744 >10000 >13440 J44 0.022 — — 0.358 >10000 >27932 J45 0.028 — — 0.398 >10000 >25125 J46 0.033 — — 2.35 >10000 >4255 J47 0.037 — — 4.73 >10000 >2114 J48 0.035 — — 70.2 >10000 >1421411 J49 0.13 — — — — — J50 0.049 — — 27.68 >10000 >361 J51 0.043 — — 1.58 >10000 >6329 J52 0.021 — — 1.43 >10000 >699 J53 0.033 — — 3.47 >10000 >2881 J54 0.028 — — 2.03 >10000 >4926 J55 0.033 — — 11.38 >10000 >878 J56 0.044 — — 30.07 >10000 >332 J57 0.045 — — 15.3 >10000 >653 J58 0.025 — — 0.497 >10000 >20120 J59 0.029 — — 1.31 >10000 >7633 J60 0.021 — — 0.797 >10000 >12547 J61 0.019 — — 1.42 >10000 >7042 J62 0.037 — — 4.85 >10000 >2061 J63 0.018 — — 0.462 >10000 >21645 J64 — — — — — — J65 — — — — — —

TABLE 10 Biochemical assay Cellular assay Selec- Selec- TYK2- JAK1- tivity pSTAT4/ pSTAT5/ tivity JH2 JH2 fold IL-12 GM-CSF fold IC50 IC50 (TYK2/ IC50 IC50 (TYK2/ Example (nM) (nM) JAK1) (nM) (nM) JAK2) M1  0.055 — — 0.174 2010 11551 M2  0.032 — — 1.04 >10000 >9615 M3  0.031 — — 0.526 8351 15876 M4  0.026 — — 0.681 >10000 >14684 M5  0.032 — — 0.189 1551 8206 M6  0.032 — — 1.21 >10000 >8264 M7  0.026 — — 0.537 >10000 >18621 M8  0.04 — — 1.64 >10000 >6097 M9  0.035 — — 7.06 >10000 >1416 M10 0.099 — — — — — M11 0.034 — — 9.03 >10000 >1107 M12 0.03 — — 9.12 >10000 >1096 M13 0.11 — — — — — M14 0.03 — — 9.46 >10000 >1057 M15 0.048 — — 10.23 >10000 >977 M16 0.048 — — — — — M17 0.041 — — 1.09 >10000 >9174 M18 0.026 — — 0.989 >10000 >10111 M19 0.032 — — 2.55 >10000 >3921 M20 0.062 — — 1.01 >10000 >9900 M21 0.035 — — 1.69 >10000 >5917 M22 0.027 — — 0.316 532 1683 M23 0.031 — — 1.08 3749 3471 M24 0.032 — — 0.487 2175 4466 M25 0.096 — — 15.17 >10000 >659 M26 0.046 — — 4.33 >10000 >2309 M27 0.035 — — 3.85 >10000 >2597 M28 0.032 — — 16.62 >10000 >601 M29 — — — — — — M30 0.049 — — 11.2 >10000 >892 M31 0.031 — — 0.828 1421 1714 M32 0.074 — — — — — M33 0.027 — — 0.648 >10000 >15432 M34 0.024 — — 0.402 >10000 >24875 M35 0.036 — — 50.24 >10000 >199

TABLE 11 Biochemical assay Cellular assay Selec- Selec- TYK2- JAK1- tivity pSTAT4/ pSTAT5/ tivity JH2 JH2 fold IL-12 GM-CSF fold IC50 IC50 (TYK2/ IC50 IC50 (TYK2/ Example (nM) (nM) JAK1) (nM) (nM) JAK2) N1 0.077 — — 0.247 2133 8635 N2 0.021 — — 0.641 >10000 >15600 N3 0.033 — — 12.63 >10000 >791 N4 0.029 — — 0.137 >10000 >72992 N5 0.039 — — 0.212 >10000 >47169 N6 0.039 — — 0.274 >10000 >36496 N7 0.024 — — 1.43 >10000 >6993

TABLE 12 Biochemical assay Cellular assay Selec- Selec- TYK2- JAK1- tivity pSTAT4/ pSTAT5/ tivity JH2 JH2 fold IL-12 GM-CSF fold IC50 IC50 (TYK2/ IC50 IC50 (TYK2/ Example (nM) (nM) JAK1) (nM) (nM) JAK2) O1 0.017 — — 0.414 1213 2929 O2 0.016 — — 1.12 7007 6265 O3 0.031 — — 6.86 8295 2109

TABLE 13 Biochemical assay Cellular assay Selec- Selec- TYK2- JAK1- tivity pSTAT4/ pSTAT5/ tivity JH2 JH2 fold IL-12 GM-CSF fold IC50 IC50 (TYK2/ IC50 IC50 (TYK2/ Example (nM) (nM) JAK1) (nM) (nM) JAK2) Q1  0.023 — — 1.76 >10000 >5681 Q2  0.021 — — 1.7 >10000 >5882 Q3  0.023 — — 1.14 >10000 >8771 Q4  0.037 — — 1.10 >10000 >9090 Q5  0.065 — — — — — Q6  0.028 — — 0.45 >10000 >22222 Q7  — — — — — — Q8  — — — — — — Q9  — — — — — — Q10 — — — — — — Q11 — — — — — — Q12 — — — — — — Q13 — — — — — — Q14 — — — — — — Q15 — — — — — — Q16 — — — — — — Q17 — — — — — — Q18 0.023 — — 0.91 >10000 >10989 Q19 0.025 — — 3.02 >10000 >3311 Q20 0.022 — — 0.16 1767 11043 Q21 0.037 — — 0.411 1572 3824 Q22 0.025 — — 0.584 3959 6779 Q23 0.028 — — 0.605 8101 13390 Q24 0.033 — — 0.559 620 1109 Q25 0.026 — — 0.530 1822 3437 Q26 0.032 — — 1.53 700 457 Q27 0.033 — — — — — Q28 0.026 — — 0.329 >10000 >30395 Q29 0.037 — — — — — Q30 0.065 — — — — — Q35 0.020 — — 0.679 1810 2665 Q36 — — — — — — Q49 0.029 — — 0.827 379 458 Q50 0.019 — — 0.626 2023 3231 Q51 0.034 — — 0.979 >10000 >10214 Q52 0.038 — — 1.33 3420 2571 Q53 0.047 — — 0.581 >10000 >17211 Q54 0.037 — — 0.560 3985 7116 Q55 0.019 — — — — — Q56 0.031 — — — — — Q57 0.031 — — — — — Q58 0.097 — — — — — Q59 0.033 — — — — — Q60 0.059 — — — — — Q61 0.022 — — — — — Q62 0.047 — — 1.79 >10000 >5586 Q63 0.051 — — 0.755 459 608 Q64 0.034 — — 4.61 >10000 >2169 Q65 0.029 — — 0.685 1642 2397 Q66 0.029 — — 0.792 3046 3845 Q73 0.025 — — 2.84 2354 828 Q75 0.024 — — 0.637 473 742 Q79 0.32 — — — — — Q86 0.031 — — 1.48 91 615 Q90 — — — 44 >10000 227 Q97 — — — 3.29 >10000 3039 Q98 0.026 — — 1.15 >10000 8695 Q99 0.033 — — — — —  Q101 0.03 — — 0.904 373 412  Q104 0.029 — — — — —  Q106 0.015 — — — — —  Q108 — — — 1.18 >10000 >8474  Q110 — — — 1.08 >10000 >9259  Q115 0.034 — — 0.302 >10000 >33112  Q119 0.031 — — 1.19 1149 965  Q120 0.032 — — — — —

TABLE 14 Biochemical assay Cellular assay Selec- Selec- TYK2- JAK1- tivity pSTAT4/ pSTAT5/ tivity JH2 JH2 fold IL-12 GM-CSF fold IC50 IC50 (TYK2/ IC50 IC50 (TYK2/ Example (nM) (nM) JAK1) (nM) (nM) JAK2) R1 0.041 — — 2.18 >10000 >4587

Binding Pose of Compounds in Tyk2 JH2 Domain

The X-ray crystal structure of human Tyk2 JH12 domain in complex with BMS986165 (PDB ID: 6NZP) was downloaded from the RCSB protein data bank and prepared by the Protein Preparation Wizard in Schrödinger 2020, including removing crystallographic waters, fixing bond orders, adding hydrogens, assigning partial charges with the OPLS3e force field, and minimizing the added hydrogens. The 3D structure of the Example B5 was processed by LigPrep module of Schrödinger 2020 at pH7.4. And then the ligand was docked into the binding pocket (with a radius of 10 Å around BMS986165 binding site) of the above prepared Tyk2 JH2 domain using Glide SP (standard precision). Standard default settings were used for other parameters.

The binding pose of Example B5 in Tyk2 JH2 domain showed importance of substituted position of methylsulfonyl group and acetamide group on the two pyridine rings, for the Tyk2 inhibitors of the present disclosure (Scheme 1). The substituted position of methylsulfonyl group was essential for potency, meta position was much better than orth position, for example, Examples B1 and B5 showed Tyk2 JH2 domain bio-chemical potency at 0.038 nM and 0.016 nM, respectively, whereas Examples B15 and B14 were 3079-fold and 5000-fold less potent, respectively, that was due to the strong interaction between methylsulfonyl group on the pyridine ring and Lys642 residue of Tyk2 (Scheme 1). The acetamide group on the other pyridine ring can also form crucial interaction with Lys642 of Tyk2. Furtherly, the substitution R of acetamide group on the other pyridine ring effected the Tyk2 inhibition potency, for example, the potency dramatically decreased when replacing R from methyl group (Example B1) to cyclopropane group (Example B20). and. In addition, the nitrogen (N) atom of the pyridine ring, which is at the adjacent position of methylsulfonyl, was essential for coplanarity of the two pyridine rings, for example, Example B5 is 2-fold more potent than Example B1 in bio-chemical assay and 40-fold more potent in cellular assay.

Biological Assay: Mouse PK Study

The pharmacokinetics of compounds were evaluated in male CD-1 mouse via Oral Administration (dose of 10 mg/kg). For oral administration study, test compounds were added in 0.5% MC in water and administrated to mice at 10 mg/kg by gavage. Blood was collected into EDTA-K2 anticoagulant tube at 15, and 30 min and 1, 2, 4, 8 and 24 h after administration. Approximately 30 μL blood was collected at each time point. And then the blood was centrifuged at 2000 g for 5 min at 4° C. using a centrifuge to obtain the plasma. The plasma sample was transferred into a tube and stored in a freezer at approximately −70° C. until the determination of concentration by LC-MS/MS. Pharmacokinetic parameters were estimated by using WinNonlin software (version 8.1, Pharsight Corporation, CA, USA) with non-compartmental method. The following pharmacokinetic parameters were calculated, whenever possible from the plasma concentration-time data: T_(max), C_(max), AUC_(last), AUC_(inf), T_(1/2) for PO administration. All animals were fasted before experiment. The results are shown in Table 15.

TABLE 15 Po dosing (10 mg/kg) Compound T_(1/2) Cmax (ng/ml) AUC_(last) (h · ng/mL) Example F22 1.48 911 2098 Example H11 2.07 8.73 19.3 Example Q25 3.01 2820 16245

The compounds disclosed herein with pyridine fused ring part showed significantly good PK. As in Table 15, taking Example Q25 with pyridine fused ring part as an example, showed significantly better PK than Examples F22 and H11. The A_(UC) (16245 h-ng/mL) and C_(max) (2820 ng/mL) data of Example Q25 in the table were at least 3-fold higher than those of Example F22 (C_(max): 911 ng/mL; A_(UC): 2098 h-ng/mL) and H11 (C_(max): 7 ng/mL; A_(UC): 19.4 h ng/mL).

It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art in any country.

In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word “comprise” or variations such as “comprises” or “comprising” is used in an inclusive sense, i.e., to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

The disclosures of all publications, patents, patent applications and published patent applications referred to herein by an identifying citation are hereby incorporated herein by reference in their entirety.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention. 

1. A compound of Formula (I)

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein X is N or CH; Y is N, NR³ or CR³; L¹ is a direct bond, —(CR^(a)R^(b))_(q)—, —O—, —S—, —S(O)—, —SO₂—, —C(O)—, C(O)O—, —OC(O)—, —NR^(a)—, —O—(CR^(a)R^(b))_(q)—, —S—(CR^(a)R^(b))_(q)—, —S(O)—(CR^(a)R^(b))_(q)—, —SO₂—(CR^(a)R^(b))_(q)—, —C(O)—(CR^(a)R^(b))_(q)—, C(O)O—(CR^(a)R^(b))_(q)—, —OC(O)—(CR^(a)R^(b))_(q)—, —NR^(a)—(CR^(a)R^(b))_(q)—, —C(O)NR^(a)—, —NR^(a)C(O)—, —NR^(a)C(O)O—, —NR^(a)C(O)NR^(b)—, —SO₂NR^(a)—, —NR^(a)SO₂—, —NR^(a)S(O)₂NR^(b)—, —NR^(a)S(O)NR^(b)—, —C(O)NR^(a)SO₂—, —C(O)NR^(a)SO—, or —C(═NR^(a))NR^(b)—, wherein q is a number of 1 to 7, and, R^(a) and R^(b) are independently hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R¹ is —C₁₋₆alkyl, -haloC₁₋₆alkyl, —C₁₋₆ alkoxy, -haloC₁₋₆ alkoxyl, —C₃₋₆ cycloalkyl, aryl, or —NR^(c)R^(d); each of R², R³, and R⁴ is independently hydrogen, cyano, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —NO₂, —OR^(e), —SO₂R^(e), —COR^(e), —CO₂R^(e), —CONR^(e)R^(f), —C(═NR^(e))NR^(f)R^(g), —NR^(e)R^(f), —NR^(e)COR^(f), —NR^(e)CONR^(f)R^(g), —NR^(e)CO₂R^(f), —NR^(e)SONR^(f)R^(g), —NR^(e)SO₂NR^(f)R^(g), or —NR^(e)SO₂R^(f), wherein each of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently and optionally substituted with at least one substituent selected from i) cyano, -oxo-, halogen, —NR^(m)R^(n), —OR^(h), —C(O)NR^(m)R; ii) heterocyclyl optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), substituted or unsubstituted —C₁₋₆alkyl, substituted or unsubstituted —C₁₋₆alkoxy or —C(O)NR^(m)R; or, iii) C₁₋₆alkyl optionally substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂ or C₁₋₆alkoxy; wherein R^(h) is hydrogen, hydroxy, —NH₂, —C₁₋₆alkyl, C₁₋₆alkyl substituted with hydroxy, or heterocyclyl, R^(e), R^(f), and R^(g) are each independently hydrogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with one to three substituents selected from cyano, -oxo-, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₃₋₆cycloalkyl optionally substituted with halogen, hydroxy or —C₁₋₆alkoxy, —C(O)NR^(m)R^(n), or heterocyclyl; R⁵ is hydrogen or C₁₋₆alkyl; Cy¹ is 6- to 12-membered aryl or 5- to 14-membered heteroaryl, or 5- to 14-membered heterocyclyl, each of which is optionally substituted with at least one substituent R^(i), R^(i) is independently halogen, cyano, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, cyano (—CN), —NO₂, —OR^(j), —SO₂R^(j), —COR^(j), —CO₂R^(k), —CONR^(j)R^(k), —C(═NR^(j))NR^(k)R^(l), —NR^(j)R^(k), —NR^(j)COR^(k), —NR^(j)CONR^(k)R^(l), —NR^(j)CO₂R^(k), —NR^(j)SONR^(k)R^(l), —NR^(j)SO₂NR^(k)R^(l), or —NR^(j)SO₂R^(k), wherein each of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, —OR^(m), —C(O)R^(m), —NR^(m)R^(n), —C₁₋₆alkyl, C₁₋₆alkoxy-, C₁₋₆alkyl substituted with —C₁₋₆alkoxy or -oxo-; R^(j), R^(k), R^(l), R^(m), R^(n) are each independently hydrogen, —C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl-, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or (R¹ and R²), or (R² and R³), or (R³ and R⁴), together with the atoms to which they are attached, form a fused ring system, said fused ring system comprises 0-4 heteroatoms selected from oxygen (O), nitrogen (N) or sulfur (S) as ring member(s) and is optionally and independently substituted with halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, C₁₋₆alkyl substituted with halogen, C₁₋₆alkoxy substituted with halogen or —C₃₋₆cycloalkyl; wherein any of said alkyl or alkoxy is optionally enriched in deuterium.
 2. (canceled)
 3. The compound of claim 1, wherein the compound of Formula (I) is compound of Formula (I-A)

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; L¹ is a direct bond, —(CR^(a)R^(b))_(q)—, —O—, —S—, —S(O)—, —SO₂—, —C(O)—, C(O)O—, —OC(O)—, —NR^(a)—, —O—(CR^(a)R^(b))_(q)—, —S—(CR^(a)R^(b))_(q)—, —S(O)—(CR^(a)R^(b))_(q)—, —SO₂—(CR^(a)R^(b))_(q)—, —C(O)—(CR^(a)R^(b))_(q)—, C(O)O—(CR^(a)R^(b))_(q)—, —OC(O)—(CR^(a)R^(b))_(q)—, —NR^(a)—(CR^(a)R^(b))_(q)—, —C(O)NR^(a)—, —NR^(a)C(O)—, —NR^(a)C(O)O—, —NR^(a)C(O)NR^(b)—, —SO₂NR^(a)—, —NR^(a)SO₂—, —NR^(a)S(O)₂NR^(b)—, —NR^(a)S(O)NR^(b)—, —C(O)NR^(a)SO₂—, —C(O)NR^(a)SO—, or —C(═NR^(a))NR^(b)—, wherein q is a number of 1 to 7, and, R^(a) and R^(b) are independently hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R¹ is —C₁₋₆alkyl, -haloC₁₋₆alkyl, —C₁₋₆ alkoxy, -haloC₁₋₆ alkoxyl, —C₃₋₆ cycloalkyl, aryl, or —NR^(m)R^(n); each of R², R³, and R⁴ is independently hydrogen, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl, -oxo-, —CN, —NO₂, —OR^(e), —SO₂R^(e), —COR^(e), —CO₂R^(e), —CONR^(e)R^(f), —C(═NR^(e))NR^(f)R^(g), —NR^(e)R^(f), —NR^(e)COR^(f), —NR^(e)CONR^(f)R^(g), —NR^(e)CO₂R^(f), —NR^(e)SONR^(f)R^(g), —NR^(e)SO₂NR^(f)R^(g), or —NR^(e)SO₂R^(f), wherein each of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently and optionally substituted with at least one substituents selected from cyano, oxo, halogen, C₁₋₆alkyl optionally substituted with halogen, —C₁₋₆alkyl substituted with hydroxy (preferably, hydroxymethyl, hydroxyethyl), —OR^(h), —C(O)NR^(m)R^(n), —NH₂, C₁₋₆alkyl substituted with NH₂ or —C₁₋₆alkyl substituted with C₁₋₆alkoxy; wherein R^(h) is hydrogen, alkyl, hydroxy-C₁₋₆alkyl or heterocyclyl, R^(e), R^(f), and R^(g) are each independently hydrogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally independently substituted with one to three substituents selected from halogen, hydroxy, cyano, or —C₁₋₆alkoxy; —C₃₋₆ cycloalkyl optionally substituted with halogen, hydroxy, or C₁₋₆alkoxy, or heterocyclyl; R⁵ is hydrogen or C₁₋₆alkyl; Cy¹ is 6- to 12-membered aryl or 5- to 14-membered heteroaryl, or 5- to 14-membered heterocyclyl, each of which is optionally substituted with at least one substituent R^(i), R^(i) is independently halogen, cyano, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO₂, —OR^(j), —SO₂R^(j), —COR^(j), —CO₂R^(k), —CONR^(j)R^(k), —C(═NR^(j))NR^(k)R^(l), —NR^(j)R^(k), —NR^(f)COR^(k), —NR^(f)CONR^(k)R^(l), —NR^(j)CO₂R^(k), —NR^(f)SONR^(k)R^(l), —NR^(j)SO₂NR^(k)R^(l), or —NR^(j)SO₂R^(k), wherein each of said —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, OR^(m), C(O)R^(m), —NR^(m)R^(n), —C₁₋₆alkyl, C₁₋₆alkoxy-, C₁₋₆alkoxy-C₁₋₆alkyl-, or oxo; R^(j), R^(k), R^(l), R^(m), R^(n) are each independently hydrogen, —C₁₋₆alkyl, —C₁₋₆alkyl substituted with C₁₋₆alkoxy, —C₂₋₆alkenyl, —C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or (R¹ and R²), or (R² and R³), or (R³ and R⁴), together with the atoms to which they are attached, form a fused ring system, said fused ring system comprises 0-4 heteroatoms selected from oxygen, nitrogen or sulfur as ring member(s) and is optionally and independently substituted with halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, -haloC₁₋₆alkyl, -haloC₁₋₆alkoxy, or —C₃₋₆cycloalkyl; wherein any of said alkyl or alkoxy is optionally enriched in deuterium.
 4. The compound of claim 3, wherein R¹ is —C₁₋₃ alkyl, —NR^(c)R^(d) or —C₃₋₆ cycloalkyl, preferably —NH₂, methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclopentyl.
 5. The compound of claim 3, wherein R² and R⁴ are each independently hydrogen, halogen, —C₁₋₆alkyl, or —C₁₋₆alkoxy, preferably hydrogen, fluoro, methyl, methoxy, ethoxy, or isopropoxy.
 6. The compound of claim 3, wherein R³ is hydrogen; cyano; halogen; —C₁₋₄ alkyl optionally substituted with at least one substituent independently selected from halogen, 3- to 6-membered heterocyclyl or —OR^(h), wherein 3- to 6-membered heterocyclyl comprises one or two heteroatoms selected from oxygen (O), nitrogen (N) or sulfur (O) as ring member(s), optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or —C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy; and R^(h) is hydrogen, alkyl, or heterocyclyl; —C₃₋₆cycloalkyl, optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, —NR^(m)R^(n), hydroxy, —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy; heterocyclyl comprising one or two heteroatoms selected from oxygen (O), nitrogen (N) or sulfur (S) as ring member(s), optionally substituted with at least one substituent independently selected from cyano, -oxo-, halogen, hydroxy, C₁₋₆alkyl, alkoxy, —NRR^(m)R^(n), or —C(O)NR^(m)R^(n), and wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy; —OR^(e), wherein R^(e) is —C₁₋₆alkyl, —C₃₋₆cycloalkyl, 3- to 6-membered heterocyclyl, or aryl, wherein i) —C₁₋₆alkyl is optionally substituted with cyano, -oxo-, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkoxy-, —C₃₋₆cycloalkyl optionally substituted with cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkyl, C₁₋₆alkoxy or —C(O)NR^(m)R^(n), 4- to 6-membered heterocyclyl optionally substituted with cyano, halogen, hydroxy, C₁₋₆alkyl or C₁₋₆alkoxy; and, ii) —C₃₋₆cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted with cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), C₁₋₆alkyl, C₁₋₆alkoxy or —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy; —C₅₋₁₀aryl; or heteroaryl comprising one oxygen (O), nitrogen (N) or sulfur (S) heteroatom as ring member, optionally substituted with at least one substitution independently selected from cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy; and wherein R^(m) and R^(n) are independently selected from hydrogen or C₁₋₃alkyl; wherein any of said alkyl or alkoxy is optionally enriched in deuterium.
 7. The compound of claim 6, wherein R³ is hydrogen; cyano; halogen; —C₁₋₄ alkyl optionally substituted with at least one substituent independently selected from halogen, 3- to 6-membered heterocyclyl or —OR^(h), wherein said 3- to 6-membered heterocyclyl comprises one or two heteroatoms selected from oxygen (O), nitrogen (N) or sulfur (O) as ring member(s), optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy, and, R^(h) is hydrogen, alkyl or heterocyclyl (preferably 3- to 6-membered heterocyclyl, e.g., tetrahydrofuranyl, thiazolidinyl); —C₃₋₆cycloalkyl, optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, —NR^(m)R^(n), hydroxy, —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy; heterocyclyl, preferably 4- to 6-membered monocyclic saturated heterocyclyl, saturated mono-spiro heterocyclyl, saturated bicyclic fused heterocyclyl, or saturated bridged heterocyclyl, comprising one or two heteroatoms selected from oxygen (O), nitrogen (N) or sulfur (S) as ring member(s), more preferably morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl or azetidinyl, optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxy, —C₁₋₆alkyl, alkoxy, —NR^(m)R^(n), or —C(O)NR^(m)R^(n), and wherein —C₁₋₆alkyl or —C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy; —OR^(e), wherein R^(e) is —C₁₋₆alkyl, —C₃₋₆cycloalkyl, 3- to 6-membered heterocyclyl (preferably 4- to 6-membered monocyclic saturated heterocyclyl comprising one oxygen heteroatom as ring member), or aryl, wherein i) —C₁₋₆alkyl is optionally substituted with cyano, -oxo-, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkoxy-, —C₃₋₆cycloalkyl optionally substituted with cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkyl, C₁₋₆alkoxy or —C(O)NR^(m)R^(n), 4- to 6-membered heterocyclyl optionally substituted with cyano, halogen, hydroxy, —C₁₋₆alkyl or —C₁₋₆alkoxy; and, ii) —C₃₋₆cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted with cyano, -oxo, halogen, hydroxy, NR^(m)R^(n), C₁₋₆alkyl, C₁₋₆alkoxy or —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy; —C₅₋₁₀aryl; or heteroaryl, preferably 5- to 6-membered heteroaryl comprising one oxygen (O), nitrogen (N) or sulfur (S) heteroatom as ring member, optionally substituted with at least one substitution independently selected from cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy; and wherein R^(m) and R^(n) are independently selected from hydrogen or C₁₋₃alkyl.
 8. The compound of claim 6, wherein R³ is hydrogen, cyano, halogen; —C₁₋₄ alkyl optionally substituted with at least one substituent independently selected from halogen, 3- to 6-membered heterocyclyl or —OR^(h), wherein said 3- to 6-membered heterocyclyl is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, thiazolidinyl or azetidinyl, each of which is optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy, and, R^(h) is hydrogen, C₁₋₆alkyl or 3- to 6-membered heterocyclyl (e.g., tetrahydrofuranyl or thiazolidinyl); —C₃₋₆cycloalkyl, optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, NR^(m)R^(n), hydroxy, —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n), hydroxy, or C₁₋₆alkoxy, wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy; heterocyclyl is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl or azetidinyl, optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxy, C₁₋₆alkyl, alkoxy, —NRR^(m)R^(n), or —C(O)NR^(m)R^(n), and wherein —C₁₋₆alkyl or —C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or —C₁₋₆alkoxy; —OR^(e), wherein R^(e) is —C₁₋₆alkyl, —C₃₋₆cycloalkyl, 4- to 6-membered monocyclic saturated heterocyclyl comprising one oxygen heteroatom as ring member, or C₆₋₁₀aryl, wherein i) —C₁₋₆alkyl is optionally substituted with deuterium, cyano, -oxo-, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkoxy-, —C₃₋₆cycloalkyl optionally substituted with cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n), 4- to 6-membered heterocyclyl optionally substituted with cyano, halogen, hydroxy, —C₁₋₆alkyl or —C₁₋₆alkoxy; and, ii) —C₃₋₆cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted with cyano, -oxo, halogen, hydroxy, NR^(m)R^(n), C₁₋₆alkyl, C₁₋₆alkoxy or —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy; —C₆₋₁₀aryl; or 5- to 6-membered heteroaryl selected from pyridinyl, pyridazinyl, pyrazinyl, thiazolyl or isoxazolyl, each of which is optionally substituted with at least one substitution independently selected from cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆ alkoxy or —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or C₁₋₆alkoxy; and wherein R^(m) and R^(n) are independently selected from hydrogen or —C₁₋₃alkyl.
 9. The compound of claim 6, wherein R³ is hydrogen, cyano, halogen; —C₁₋₄ alkyl optionally substituted with at least one substituent independently selected from halogen, hydroxy, C₁₋₃alkoxy, thiazolidin-3-yl optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), or —C₁₋₃alkyl; C₃₋₆cycloalkyl, optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, —NR^(m)R^(n), hydroxy, —C₁₋₆alkyl, or —C₁₋₆alkoxy, wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or —C₁₋₃alkoxy; heterocyclyl is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl or azetidinyl, optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxy, C₁₋₆alkyl, alkoxy, —NR^(m)R^(n), or —C(O)NR^(m)R^(n), and wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or —C₁₋₆alkoxy; —OR^(e), wherein R^(e) is —C₁₋₆alkyl, —C₃₋₆cycloalkyl, 4- to 6-membered monocyclic saturated heterocyclyl comprising one oxygen heteroatom as ring member, or C₆₋₁₀aryl, wherein i) —C₁₋₆alkyl is optionally substituted with cyano, -oxo-, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkoxy-, —C₃₋₆cycloalkyl optionally substituted with cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n), 4- to 6-membered heterocyclyl optionally substituted with cyano, halogen, hydroxy, —C₁₋₆alkyl or —C₁₋₆alkoxy; and, ii) —C₃₋₆cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted with cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆alkoxy or —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or —C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or —C₁₋₆alkoxy; —C₆₋₁₀aryl; or 5- to 6-membered heteroaryl selected from pyridinyl, pyridazinyl, pyrazinyl, thiazolyl or isoxazolyl, each of which is optionally substituted with at least one substitution independently selected from cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₆alkyl, —C₁₋₆ alkoxy or —C(O)NR^(m)R^(n), wherein —C₁₋₆alkyl or —C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or —C₁₋₆alkoxy; and wherein R^(m) and R^(n) are independently selected from hydrogen or —C₁₋₃alkyl.
 10. The compound of claim 6, wherein R³ is hydrogen, cyano, halogen; methyl, ethyl, propyl or butyl, each of which optionally substituted with at least one substituent independently selected from halogen, hydroxy, methoxy, ethoxy, propoxy, or 2,4-dioxothiazolidin-3-yl; cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, —NR^(m)R^(n), hydroxy, —C₁₋₃alkyl, or —C₁₋₃alkoxy, wherein —C₁₋₃alkyl or C₁₋₃alkoxy is optionally substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₃alkyl or —C₁₋₃alkoxy; heterocyclyl is selected from morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, pyrrolidine-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 1,4-dioxan-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, azetidin-1-yl, azetidine-2-yl, azetidin-3-yl, 5-azaspiro[2.4]heptanyl, 3-azabicyclo[3.1.0]hexan-3-yl or 2-azabicyclo[3.1.0]hexan-2-yl, each of which is optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxy, —C₁₋₆alkyl, —C₁₋₆ alkoxy, —NR^(m)R^(n), or —C(O)NR^(m)R^(n), and wherein —C₁₋₆alkyl or C₁₋₆alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₆alkyl or —C₁₋₆alkoxy; —OR^(e), wherein R^(e) is i) methyl, ethyl, propyl (iso-propyl), butyl, pentyl or hexyl, each of which is optionally substituted with deuterium, cyano, -oxo-, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₃alkoxy-, —C₃₋₆cycloalkyl optionally substituted with cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₃alkyl, —C₁₋₃alkoxy or —C(O)NR^(m)R^(n), or 4- to 6-membered heterocyclyl optionally substituted with cyano, halogen, hydroxy, —C₁₋₃alkyl or —C₁₋₃alkoxy; or, ii) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 1,4-dioxan-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, azetidin-1-yl, azetidine-2-yl or azetidin-3-yl, each of which is optionally substituted with cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₃alkyl, —C₁₋₃alkoxy or —C(O)NR^(m)R^(n), wherein —C₁₋₃alkyl or —C₁₋₃alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₃alkyl or —C₁₋₃alkoxy; —C₆₋₁₀aryl; or 5- to 6-membered heteroaryl selected from pyridin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-1-yl, pyridazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-1-yl, pyrazin-2-yl, thiazol-2-yl, thiazol-3-yl, thiazol-4-yl, isoxazol-2-yl, isoxazol-3-yl or isoxazol-4-yl, each of which is optionally substituted with at least one substitution independently selected from cyano, -oxo, halogen, hydroxy, —NR^(m)R^(n), —C₁₋₃alkyl, —C₁₋₃ alkoxy or —C(O)NR^(m)R^(n), wherein —C₁₋₃alkyl or —C₁₋₃alkoxy is substituted with at least one substitution independently selected from cyano, halogen, hydroxy, —NH₂, —C₁₋₃alkyl or C₁₋₃alkoxy; and wherein R^(m) and R^(n) are independently selected from hydrogen or —C₁₋₃alkyl.
 11. The compound of claim 6, wherein R³ is Hydrogen; Methyl, 1-methoxyethyl, 2-hydroxypropan-2-yl, 1-methoxyethyl, or (2,4-dioxothiazolidin-3-yl)methyl; Isopropoxy, methoxy-d3, methoxy, ethoxy, difluoromethoxy, 2-methoxyethoxy, 2-methoxy-2-methylpropoxy, 2-hydroxy-2-methylpropoxy, cyclopropylmethoxy, (1,4-dioxan-2-yl)methoxy, cyclobutoxy, (4-hydroxycyclohexyl)oxy, (cis-4-hydroxycyclohexyl)oxy, (trans-4-hydroxycyclohexyl)oxy, (4-methoxycyclohexyl)oxy, (cis-4-methoxycyclohexyl)oxy, (trans-4-methoxycyclohexyl)oxy, (3-methyloxetan-3-yl)methoxy, 2-methyl-2-morpholinopropoxy; Cyano 3-methoxycyclobutyl, (trans)-3-methoxycyclobutyl, (cis)-3-methoxycyclobutyl, 2,2-dichlorocyclopropyl, or 1-cyanocyclopropyl; Morpholino, 3-methyl-morpholino, 3(R)-methyl-morpholino, 3(S)-methyl-morpholino, 3,3-dimethylmorpho; tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, (R)-tetrahydro-2H-pyran-3-yl, (S)-tetrahydro-2H-pyran-3-yl, 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl; 3-methoxypyrrolidin-1-yl, 3(R)-methoxypyrrolidin-1-yl, 3(S)-methoxypyrrolidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl, 3-(2-hydroxyethoxy)pyrrolidin-1-yl, 3-(trifluoromethoxy)pyrrolidin-1-yl, 3(R)-(trifluoromethoxy)pyrrolidin-1-yl, 3(S)-(trifluoromethoxy)pyrrolidin-1-yl, 2-(aminocarbonyl)pyrrolidin-1-yl, 2(R)-(aminocarbonyl)pyrrolidin-1-yl, 2(S)-(aminocarbonyl)pyrrolidin-1-yl, 3-(methoxymethyl)pyrrolidin-1-yl, 3(R)-(methoxymethyl)pyrrolidin-1-yl, 3(S)-(methoxymethyl)pyrrolidin-1-yl, 3-cyano-4-hydroxypyrrolidin-1-yl, cis-3-cyano-4-hydroxypyrrolidin-1-yl, trans-3-cyano-4-hydroxypyrrolidin-1-yl, 3-cyano-4-methoxypyrrolidin-1-yl, cis-3-cyano-4-methoxypyrrolidin-1-yl, trans-3-cyano-4-methoxypyrrolidin-1-yl, 2-(methoxymethyl)pyrrolidin-1-yl, 2(R)-(methoxymethyl)pyrrolidin-1-yl, 2(S)-(methoxymethyl)pyrrolidin-1-yl, 3-methylpyrrolidin-1-yl, 3(R)-methylpyrrolidin-1-yl, 3(S)-methylpyrrolidin-1-yl, pyrrolidin-1-yl, 3-(cyanomethoxy)pyrrolidin-1-yl; 5-azaspiro[2.4]heptan-5-yl; tetrahydrofuran-3-yl; 3-methoxyazetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl; 1,4-dioxan-2-yl; 4-aminotetrahydro-2H-pyran-4-yl, 4-(aminomethyl)tetrahydro-2H-pyran-4-yl, 4-methoxypiperidin-1-yl, 4-hydroxy-4-methylpiperidin-1-yl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 3-methoxypiperidin-1-yl, 3(R)-methoxypiperidin-1-yl, 3(S)-methoxypiperidin-1-yl, 3-ethoxypiperidin-1-yl, 3(R)-ethoxypiperidin-1-yl, 3(S)-ethoxypiperidin-1-yl; 3-cyano-2-azabicyclo[3.1.0]hexan-2-yl, (3R)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl, (3S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl; 4-methylpyridin-3-yl, 5-methylpyridazin-4-yl, 5-methoxypyridazin-4-yl, 3,5-dimethylisoxazol-4-yl, 4-methoxypyridin-3-yl, 4-(2-hydroxypropan-2-yl)pyridin-3-yl, 6-cyanopyridin-3-yl, 4-cyanopyridin-3-yl, 2-cyanopyridin-3-yl, 3-methylpyrazin-2-yl, 5-cyanopyridazin-4-yl, 5-fluoropyridazin-4-yl, 4-fluoropyridin-3-yl, 4-isopropylpyridin-3-yl, 4-(1-hydroxyethyl)pyridin-3-yl, 4-(1-methoxyethyl)pyridin-3-yl, pyridin-2-yl, or thiazol-4-yl.
 12. The compound of claim 3, wherein (R¹ and R²), or (R² and R³), or (R³ and R⁴), together with the atoms to which they are attached, form a fused 5- to 7-membered ring system, said fused ring system comprises 0-2 oxygen heteroatoms as ring member(s) and is optionally and independently substituted with halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, -haloC₁₋₆alkyl, -haloC₁₋₆alkoxy, or —C₃₋₆cycloalkyl.
 13. The compound of claim 3, wherein R¹ and R² together with the atoms to which they are attached, form a fused ring system selected from

or R² and R³, together with the atoms to which they are attached, form a fused ring system

R³ and R⁴, together with the atoms to which they are attached, form a fused ring system selected from

and wherein each of fused ring system is optionally and independently substituted with halogen, —C₁₋₆alkyl, —C₁₋₆alkoxy, -haloC₁₋₆alkyl, -haloC₁₋₆alkoxy, or —C₃₋₆cycloalkyl.
 14. The compound of claim 3, wherein L is a bond.
 15. The compound of claim 3, wherein Cy¹ is a. a 5- to 7-membered monocyclic heterocyclyl or heteroaryl comprising 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen or sulfur as ring member(s), or b. 7- to 14-membered bicyclic or tricyclic heterocyclyl or heteroaryl having 1, 2, or 3 heteroatoms selected from oxygen, nitrogen or sulfur as ring member(s), each of which is optionally substituted with at least one substituent R^(i).
 16. The compound of claim 15, wherein Cy¹ is a. said 5- to 7-membered monocyclic heteroaryl comprising 1, 2, 3 or 4 heteroatom(s) selected from oxygen (O), nitrogen (N) or sulfur (S) as ring member(s), preferably pyrazolyl, triazolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, pyridinyl, pyridazinyl, pyrazinyl or pyrimidinyl, said monocyclic heteroaryl is optionally substituted with one or two substituents selected from i. halogen; ii. cyano; iii. —C₁₋₆alkyl optionally substituted with halogen, hydroxy, —C₁₋₆alkoxy, —C(O)R^(m) (preferably R^(m) is morpholinyl), or —NR^(m)R^(n); iv. heterocyclyl optionally substituted with halogen, C₁₋₆alkyl-, —C₁₋₆alkyl substituted with —C₁₋₆alkoxy, or oxo; preferably said heterocyclyl is selected from tetrahydrofuranyl (preferably tetrahydrofuran-3-yl), morpholinyl (preferably morpholino), 2-oxa-5-azabicyclo[2.2.1]heptanyl (preferably 2-oxa-5-azabicyclo[2.2.1]heptan-2-yl), 8-oxa-3-azabicyclo[3.2.1]octanyl (preferably 8-oxa-3-azabicyclo[3.2.1]octan-8-yl), isoindolinyl (preferably isoindolin-2-yl), each of which is optionally substituted with methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, n-butyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, or oxo; v. —C₃₋₆cycloalkyl optionally substituted with halogen, -oxo, —C₁₋₆alkyl, C₁₋₆alkoxy-, or —C₁₋₆alkyl substituted with —C₁₋₆alkoxy; or vi. —OR^(j), wherein R^(j) is —C₁₋₆alkyl, —C₁₋₆alkyl substituted with —C₁₋₆alkoxy, or heterocyclyl; vii. oxo; b. said 7- to 14-membered bicyclic or tricyclic heteroaryl comprising 1, 2, or 3 heteroatom(s) selected from oxygen, nitrogen or sulfur as ring member(s), preferably benzoimidazolyl, imidazopyrimidinyl, pyrazolopyrazinyl, pyrazolopyrimidinyl, benzothiophenyl, benzothiazolyl, benzoisoxazolyl, benzooxazolyl, benzoisothiazolyl, imidazopyridazinyl, imidazopyridazinyl; dihydro-4H-furo[3,2-c]pyranyl, 6,7-dihydro-4H-thieno[3,2-c]pyranyl, 2,3-dihydropyrazolo[5,1-b]oxazolyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 1,3a,4,6,7,7a-hexahydropyrano[4,3-c]pyrazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2,3-dihydropyrazolo[5,1-b]oxazolyl, 2,3-dihydropyrazolo[5,1-b]oxazolyl, 1,3a,4,6,7,7a-hexahydropyrano[4,3-c]pyrazolyl, 6,7-dihydro-4H-pyrano[4,3-d]thiazolyl, [1,3]dioxolo[4,5-c]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-c]pyridinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazinyl, or 2H-pyrido[3,2-b][1,4]oxazin-4 (3H)-yl, each of which is optionally substituted with halogen, —C₁₋₆alkyl, —NH₂, or —C(O)R^(m), wherein R^(m) is C₁₋₆alkyl; and wherein any of said alkyl is optionally enriched in deuterium.
 17. The compound of claim 15, wherein Cy¹ is a 7- to 14-membered bicyclic heteroaryl which is a pyridinyl, pyrazolyl, thienyl, or thiazolyl ring fused with a 5- or 6-membered heterocyclyl ring, wherein said 5- or 6-membered heterocyclyl ring comprising one or two heteroatoms selected from oxygen or nitrogen as ring member(s) and said 5- or 6-membered heterocyclyl ring is optionally substituted with one or two C₁₋₆alkyl or oxo, preferably two C₁₋₆alkyl, more preferably two methyl, most preferably two methyl on the same carbon atom; any of said alkyl or alkoxy is optionally enriched in deuterium.
 18. The compound of claim 15, wherein Cy¹ is


19. A compound according to claim 3, wherein the compound is selected from: N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(pyridazin-3-yl)pyridin-2-yl)acetamide; N-[4-[(3-methanesulfonylphenyl)amino]-5-(oxolan-2-yl)pyridin-2-yl]acetamide; N-(5-(1H-imidazol-4-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(5-methylpyrazin-2-yl)-4-((3-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide; N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(pyrazin-2-yl)pyridin-2-yl)acetamide; N-(5-(2,6-dimethylpyrimidin-4-yl)-4-((3-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide; N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-4-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(furan-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-1,2,4-triazol-3-yl)-4-((3-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide; N-(4-((3-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)acetamide; N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1H-pyrazol-1-yl)pyridin-2-yl)acetamide; N-(4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-(2-morpholino-2-oxoethyl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-(2-hydroxyethyl)-1H-pyrazol-3-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(6-cyano-4′-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-cyano-4′-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(1H-imidazol-1-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-cyclobutyl-1H-pyrazol-3-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2-aminopropan-2-yl)-4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(1H-imidazol-4-yl)-4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1H-imidazol-4-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1H-imidazol-4-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyridazin-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide; N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide; N-(4-((4-((2S,6R)-2,6-dimethylmorpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide; N-(5-(6-methoxypyridazin-3-yl)-4-((6-(methylsulfonyl)-[1,3]dioxolo[4,5-c]pyridin-4-yl)amino)pyridin-2-yl)acetamide; N-(5-(6-isopropoxypyridazin-3-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(6-isopropoxypyridazin-3-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(6-isopropoxypyridazin-3-yl)-4-(4-(methoxy-d3)-6-(methylsulfonyl)pyridin-2-ylamino)pyridin-2-yl)acetamide; N-(4′-((3-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4-((6-(methylsulfonyl)pyridin-2-yl)amino)-[3,3′-bipyridin]-6-yl)acetamide; N-(4′-(phenylamino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((6-sulfamoylpyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4-(methoxymethyl)-4′-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4-(2-hydroxypropan-2-yl)-4′-((3-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4-(2-hydroxypropan-2-yl)-4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-(methylsulfonyl)phenyl)amino)-5-morpholino-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,2-dimethylmorpholino)-4′-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-methoxyphenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((2-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4′-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4-chloro-5-(2-hydroxypropan-2-yl)-4′-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-(methoxymethyl)morpholino)-[2,3′-bipyridin]-6′-yl)acetamide; N4′-(3-(methylsulfonyl)phenyl)-[2,3′-bipyridine]-4′,6′-diamine; N-(4′-((3-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)cyclopropanecarboxamide; (S)—N-(4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-((tetrahydrofuran-3-yl)oxy)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-((tetrahydrofuran-3-yl)oxy)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-((tetrahydrofuran-3-yl)oxy)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,5-dimethylmorpholino)-4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(cis-2,6-dimethylmorpholino)-4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-((cis)-2,6-dimethylmorpholino)-4′-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-((cis)-2,6-dimethylmorpholino)-4′-((3-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-((cis)-2,6-dimethylmorpholino)-4′-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-((cis)-2,6-dimethylmorpholino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl)amino)-5-((cis)-2,6-dimethylmorpholino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-((trans)-2,6-dimethylmorpholino)-4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(Cis-2,6-dimethylmorpholino)-4′-((7-(methylsulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-5-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-((cis)-2,6-dimethylmorpholino)-4′-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-((cis)-2,6-dimethylmorpholino)-4′-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-((cis)-2,6-dimethylmorpholino)-4′-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-((cis)-2,6-dimethylmorpholino)-4′-((4-((R)-2-hydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-((R)-sec-butoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-((cis)-2,6-dimethylmorpholino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-((cis)-2,6-dimethylmorpholino)-4′-((3-methoxy-5-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-((cis)-2,6-dimethylmorpholino)-4′-((3-fluoro-5-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-cyano-5-(methylsulfonyl)phenyl)amino)-5-((cis)-2,6-dimethylmorpholino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(cis-2,6-dimethylmorpholino)-4′-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-((cis)-2,6-dimethylmorpholino)-4′-((4-(methoxy-d3)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(cis-2,6-dimethylmorpholino)-4′-((4-(1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-((cis)-2,6-dimethylmorpholino)-4′-((4-((R or S)-1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-((cis)-2,6-dimethylmorpholino)-4′-((4-((R or S)-1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(cis-2,6-dimethylmorpholino)-4′-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(cis-2,6-dimethylmorpholino)-4′-((6-(methylsulfonyl)pyrazin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(cis-2,6-dimethylmorpholino)-4′-((4-((S)-3-methylmorpholino)-6-(methylsulfon-yl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)ace-tamide; N-(5-(cis-2,6-dimethylmorpholino)-4′-((4-((R)-3-methylmorpholino)-6-(methylsulfon-yl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)ace-tamide; N-(5-(cis-2,6-dimethyl morpholino)-4′-((4-(3-methoxy azetidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-methoxyethoxy)-4′-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-methoxyethoxy)-4′-((3-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-methoxyethoxy)-4′-((3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-methoxyethoxy)-4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-methoxyethoxy)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-methoxyethoxy)-[2,3′-bipyridin]-6′-yl)acetamide; (R)—N-(5-(2-methoxyethoxy)-4′-((4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-methoxyethoxy)-4′-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-methoxyethoxy)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(2-methoxyethoxy)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-methoxyethoxy)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(methoxymethyl)-4′-((3-(methylsulfonyl) phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(methoxymethyl)-4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; (R)—N-(5-(methoxymethyl)-4′-((4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(methoxymethyl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(methoxymethyl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(methoxymethyl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(methoxymethyl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-((1r,3r)-3-hydroxycyclobutoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(methoxymethyl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(methoxymethyl)-4′-((4-(methoxymethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-(methylsulfonyl)phenyl)amino)-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-methyl-5-(methylsulfonyl)phenyl)amino)-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-cyano-5-(methylsulfonyl)phenyl)amino)-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-((trans)-3-hydroxycyclobutoxy)-5-(methylsulfonyl)phenyl)amino)-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-(2-hydroxyethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-(2-methoxyethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamidecarboxamide; N-(4′-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-fluoro-4′-((3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-fluoro-4′-((3-isopropoxy-5-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-fluoro-4′-((3-((trans)-3-hydroxycyclobutoxy)-5-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-fluoro-4′-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-fluoro-4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-fluoro-4′-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-fluoro-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamide; (S)—N-(4′-((4-(2-hydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-fluoro-4′-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3,4-dimethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-fluoro-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-fluoro-4′-((4-(methoxy-d3)-6-(methylsulfonyl)pyridine-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-cyclopropyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-fluoro-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-(methylsulfonyl)phenyl)amino)-5-(3-oxomorpholino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3-oxomorpholino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3-oxomorpholino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3-oxomorpholino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((3-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((3-(methylsulfonyl)-5-(trifluoro methyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((3-methoxy-5-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-(trans)-3-hydroxycyclobutoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((6-(methylsulfonyl)-4-(oxetan-3-ylmethoxy)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((4-(methoxymethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-cyano-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((3-(2-methoxyethoxy)-5-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((3-(methoxymethyl)-5-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((3-(3-hydroxypyrrolidin-1-yl)-5-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((3-(methylsulfonyl)-5-(trifluoromethoxy)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-fluoro-5-(methylsulfonyl)phenyl)amino)-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-cyano-5-(methylsulfonyl)phenyl)amino)-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((3-methyl-5-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-cyclopropoxy-5-(methylsulfonyl)phenyl)amino)-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((3-isopropoxy-5-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((3-(difluoromethyl)-5-(methylsulfonyl)phenyl)amino)-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((4-(2-hydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((6-(methylsulfonyl)-4-(oxetan-3-yloxy)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-(cis-3-hydroxycyclobutoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((4-(3-methoxycyclobutoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-cyclobutoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((3-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((5-fluoro-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((2-methyl-5-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4′-((6-(ethylsulfonyl)-4-isopropoxypyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((7-(methylsulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-5-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; (R)—N-(5-(2-hydroxypropan-2-yl)-4′-((4-(2-hydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((4-isobutoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; (S)—N-(4′-((4-(sec-butoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide; (R)—N-(4′-((4-(sec-butoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4′-((3-isopropoxy-5-(methylsulfonyl)phenyl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-sulfamoylpyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((6-(ethylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((3-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide; N-(4-((3-cyano-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((3-methyl-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide; N-(4-((3-methoxy-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((3-(methylsulfonyl)-5-(trifluoromethoxy)phenyl)amino)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (R)—N-(4-((4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-((trans)-3-hydroxycyclobutoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-((cis)-3-hydroxycyclobutoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(3-methoxycyclobutoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(methoxymethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(cyanomethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(i-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(i-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-(oxetan-3-yloxy)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((3-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(2-hydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(i-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-(oxetan-3-ylmethoxy)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-cyano-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(i-methyl-1H-pyrazol-3-yl)-4-((3-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((6-(cyclopropylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((6-(isopropylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((3-fluoro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((3-(difluoromethyl)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)amino)pyridin-2-yl)acetamide; N-(4-((3-(methoxymethyl)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((3-(2-methoxyethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((3-cyclopropoxy-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((3-((trans)-3-hydroxycyclobutoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-phenylpyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-phenoxypyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-chloro-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(difluoromethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-cyclobutoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(cyclopentyloxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (R)—N-(4-((4-(2-hydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(2,3-dihydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((3-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((5-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((5-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((6-(ethylsulfonyl)-4-isopropoxypyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((5-fluoro-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (S)—N-(4-((3-(2-hydroxypropoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((3-(2-hydroxyethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (R)—N-(4-((3-(2-hydroxypropoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(difluoromethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-isobutoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (S)—N-(4-((4-(sec-butoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((3-(difluoromethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((3-(difluoromethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((7-(methylsulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-5-yl)amino)pyridin-2-yl)acetamide; (R)—N-(4-((4-(sec-butoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-cyclopropyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-cyclopropyl-1H-pyrazol-3-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-cyclopropyl-1H-pyrazol-3-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-cyclopropyl-1H-pyrazol-3-yl)-4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((4-(methoxymethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((3-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide; N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((3-methoxy-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide; N-(4-((3-cyano-5-(methylsulfonyl)phenyl)amino)-5-(1-ethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((3-methyl-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide; N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((3-(methoxymethyl)-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide; N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)amino)pyridin-2-yl)acetamide; N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((3-(2-methoxyethoxy)-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide; N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((3-(2-hydroxyethoxy)-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide; N-(4-((3-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-ethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(cyclopentyloxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-ethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-ethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((3-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-isopropyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-isopropyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-isopropyl-1H-pyrazol-3-yl)-4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-isopropyl-1H-pyrazol-3-yl)-4-((3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)amino)pyridin-2-yl)acetamide; N-(4-((3-isopropoxy-5-(methylsulfonyl)phenyl)amino)-5-(1-isopropyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-isopropyl-1H-pyrazol-3-yl)-4-((3-methoxy-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide; N-(4-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-isopropyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((3-(2-hydroxyethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-isopropyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (R)—N-(4-((3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)amino)-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (S)—N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (R)—N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (R)—N-(4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((3-(2-hydroxyethoxy)-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide; N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (R)—N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(2-hydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridine-2-yl)amino)pyridin-2-yl)acetamide; N-(5-([1,3]dioxolo[4,5-b]pyridin-5-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-7-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(imidazo[1,2-b]pyridazin-6-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(4-acetyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(benzo[b]thiophen-2-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-4-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-([1,3]dioxolo[4,5-b]pyridin-5-yl)-4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-([1,3]dioxolo[4,5-b]pyridin-5-yl)-4-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-([1,3]dioxolo[4,5-b]pyridin-5-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyridin-2-yl)acetamide; N-(5-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-((1,4-dioxan-2-yl)methoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-6-yl)-4-((6-(methylsulfonyl)pyrazin-2-yl)amino)pyridine-2-yl)acetamide; N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-6-yl)-4-((4-(2-hydroxypropan-2-yl)-6-(methylsulfonyl)pyridine-2-yl)amino)pyridine-2-yl)acetamide; N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-6-yl)-4-((5-fluoro-4-methyl-6-(methylsulfonyl)pyridine-2-yl)amino)pyridine-2-yl)acetamide; N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-morpholinopyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-morpholinopyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(methoxy-d3)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((3,4-dimethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methyl-morpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)-pyridin-2-yl)acetamide; (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methyl-morpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)-pyridin-2-yl)acetamide; N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(methoxy-d3)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (R)—N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methylmorpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (S)—N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methylmorpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (S)—N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (R)—N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-(4-aminotetrahydro-2H-pyran-4-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(4-((4-(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methoxyazetidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (R/S)—N-(4-((4-(1,4-dioxan-2-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; (S/R)—N-(4-((4-(1,4-dioxan-2-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(4-methoxypiperidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-((cis)-3-methoxycyclobutyl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-((trans)-3-methoxycyclobutyl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(4-hydroxy-4-methylpiperidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-hydroxy-3-methylazetidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyrid-in-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-hydroxy-3-methylpyrrolidin-1-yl)-6-(methyl sulfonyl)pyridin-2-yl)amino)pyridin-2-yl) acetamide; N-(6-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-5-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridazin-3-yl)acetamide; (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-(2-hydroxyethoxy)pyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl) acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-2-yl)amino)pyridin-2-yl) acetamide; (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-(2-hydroxyethoxy)pyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6′-(methylsulfonyl)-[3,4′-bipyridin]-2′-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-cyano-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6-(methylsulfonyl)-3-oxo-3,4-dihydropyrazin-2-yl)amino)pyridin-2-yl)acetamide; (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methoxypiperidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methoxypiperidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-ethoxypiperidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-ethoxypiperidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(3-(trifluoromethoxy)pyrrolidin-1-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(3-(trifluoromethoxy)pyrrolidin-1-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (S)-1-(2-((2-acetamido-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-4-yl)amino)-6-(methylsulfonyl)pyridin-4-yl)pyrrolidine-2-carboxamide; (R)-1-(2-((2-acetamido-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-4-yl)amino)-6-(methylsulfonyl)pyridin-4-yl)pyrrolidine-2-carboxamide; (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-(methoxymethyl)pyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-(methoxymethyl)pyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((5-(3-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((5-(3-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(5-methylpyridazin-4-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(5-methoxypyridazin-4-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-(cis-3-cyano-4-hydroxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(4-((4-(trans-3-cyano-4-hydroxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(4-((4-(cis-3-cyano-4-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(4-((4-(trans-3-cyano-4-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(2-(methoxymethyl)pyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(2-(methoxymethyl)pyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((3-(3-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((3-(3-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; cis-N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-((cis-4-hydroxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-((trans-4-hydroxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-((cis-4-methoxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-((trans-4-methoxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(5-azaspiro[2.4]heptan-5-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-((3-methyloxetan-3-yl)methoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3,5-dimethylisoxazol-4-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-((2,4-dioxothiazolidin-3-yl)methyl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methoxy-6′-(methylsulfonyl)-[3,4′-bipyridin]-2′-yl)amino)pyridin-2-yl)acetamide; (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methylpyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methylpyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(pyrrolidin-1-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(2-hydroxypropan-2-yl)-6′-(methylsulfonyl)-[3,4′-bipyridin]-2′-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-(3-azabicyclo[3.1.0]hexan-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; (S)—N-(4-((4-(3-(cyanomethoxy)pyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(4-((6-cyano-6′-(methylsulfonyl)-[3,4′-bipyridin]-2′-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(4-((2-cyano-6′-(methylsulfonyl)-[3,4′-bipyridin]-2′-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methylpyrazin-2-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (R)—N-(4-((4-(2,2-dichlorocyclopropyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; (S)—N-(4-((4-(2,2-dichlorocyclopropyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(4-((4-(5-cyanopyridazin-4-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(4-((4-cyano-6′-(methylsulfonyl)-[3,4′-bipyridin]-2′-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(5-fluoropyridazin-4-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-fluoro-6′-(methylsulfonyl)-[3,4′-bipyridin]-2′-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6′-(methylsulfonyl)-[2,4′-bipyridin]-2′-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(thiazol-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-(1-cyanocyclopropyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(4-((4-((3R)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(4-((4-((3S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(2-methyl-2-morpholinopropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(2-methoxy-2-methylpropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(2-hydroxy-2-methylpropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3,3-dimethylmorpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-isopropyl-6′-(methylsulfonyl)-[3,4′-bipyridin]-2′-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(1-hydroxyethyl)-6′-(methylsulfonyl)-[3,4′-bipyridin]-2′-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(1-methoxyethyl)-6′-(methylsulfonyl)-[3,4′-bipyridin]-2′-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-[1,3]dioxolo[4,5-c]pyridin-4-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((7-(methylsulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-5-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-(difluoromethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(4-((4-cyclobutoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; N-(5-(2,2-bis(methyl-d3)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-bis(methyl-d3)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(methoxy-d3)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(4,4-dimethyl-4,5-dihydrothiazol-2-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(4,4-dimethyl-4,5-dihydrothiazol-2-yl)-4-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1,3a,4,6,7,7a-hexahydropyrano[4,3-c]pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide; N-(5-([1,3]dioxolo[4,5-c]pyridin-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-([1,3]dioxolo[4,5-c]pyridin-4-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(benzo[d][1,3]dioxol-4-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(imidazo[1,2-a]pyrimidin-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-methyl-1,4-dihydrochromeno[4,3-c]pyrazol-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(imidazo[2′,1′:2,3]thiazolo[5,4-b]pyridin-7-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrano[2,3-b]pyridin-7-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4′-((4,4-dioxido-2,3-dihydro-[1,4]oxathiino[3,2-b]pyridin-6-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(4-((4,4-dioxido-2,3-dihydro-[1,4]oxathiino[3,2-b]pyridin-6-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(imidazo[1,2-b]pyridazin-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((7-(methylsulfonyl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-5-yl)amino)pyridin-2-yl)acetamide; N-(4-((5,5-dioxido-3,4-dihydro-2H-[1,4]oxathiepino[3,2-b]pyridin-7-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(2-hydroxypropan-2-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(1-hydroxycyclopropyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(2-hydroxy-2-methylpropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(3-hydroxy-2,2-dimethylpropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(imidazo[1,5-b]pyridazin-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-(3-hydroxytetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((4-(1-methyl-1H-pyrazol-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-((1-hydroxycyclopropyl)methoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-((1-methoxycyclopropyl)methoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-morpholinopyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(benzo[d]thiazol-2-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((1,1-dioxido-3,4-dihydro-2H-thiopyrano[2,3-b]pyridin-7-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((7-(methylsulfonyl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-5-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-[1,3]dioxolo[4,5-c]pyridin-4-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)imidazo[1,2-a]pyrazin-8-yl)amino)pyridin-2-yl)acetamide; N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((5-(methylsulfonyl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((4-(2-hydroxypropan-2-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((6-(methylsulfonyl)-4-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((4-(1-hydroxycyclopropyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((4-(2-hydroxy-2-methylpropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((4-(3-hydroxy-2,2-dimethylpropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((4-(3-methoxytetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((4-(3-hydroxytetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((4-(1-methyl-1H-pyrazol-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((4-((1-hydroxycyclopropyl)methoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((4-((1-methoxycyclopropyl)methoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((6-(methylsulfonyl)-4-morpholinopyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((5,5-dioxido-3,4-dihydro-2H-[1,4]oxathiepino[3,2-b]pyridin-7-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((1,1-dioxido-3,4-dihydro-2H-thiopyrano[2,3-b]pyridin-7-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((7-(methylsulfonyl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-5-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((6-(methylsulfonyl)-[1,3]dioxolo[4,5-c]pyridin-4-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((6-(methylsulfonyl)imidazo[1,2-a]pyrazin-8-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((5-(methylsulfonyl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(benzo[d][1,3]dioxol-4-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(benzo[d]isoxazol-3-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(benzo[d]isothiazol-3-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(benzo[b]thiophen-2-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(imidazo[1,2-a]pyrimidin-2-yl)pyridin-2-yl)acetamide; N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1,4-dihydrochromeno[4,3-c]pyrazol-6-yl)pyridin-2-yl)acetamide; N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(imidazo[2′,1′:2,3]thiazolo[5,4-b]pyridin-7-yl)pyridin-2-yl)acetamide; N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1,4-dihydropyrazolo[3′,4′:4,5]pyrano[2,3-b]pyridin-7-yl)pyridin-2-yl)acetamide; N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(6-oxo-1,6-dihydropyridazin-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(6-oxopyridazin-1 (6H)-yl)pyridin-2-yl)acetamide; N-(5-(6-((2S,6R)-2,6-dimethylmorpholino)pyridazin-3-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3-oxo-8,9-dihydropyrano[4,3,2-de]phthalazin-2 (3H)-yl)pyridin-2-yl)acetamide; N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(7-methyl-3-oxo-8,9-dihydro-3H-pyrido[4,3,2-de]phthalazin-2 (7H)-yl)pyridin-2-yl)acetamide; N-(4′-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-oxoisoindolin-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(5′H,7′H-spiro[cyclopropane-1,6′-pyrazolo[5,1-b][1,3]oxazin]-2′-yl)pyridin-2-yl)acetamide; N-(4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyridin-2-yloxy)pyridin-2-yl)acetamide; N-(5-(1H-imidazol-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(4-(2-hydroxypropan-2-yl)furan-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(furan-2-yl)-4-((4-(3-methoxytetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(1H-benzo[d]imidazol-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(3-fluoro-5-(2-hydroxypropan-2-yl)-4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(3-fluoro-5-(2-hydroxypropan-2-yl)-4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2-hydroxypropan-2-yl)-4-methyl-4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((6-(methylsulfonyl)-4-((tetrahydrofuran-3-yl)methoxy)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(2,6-dimethylmorpholino)-4′-((6-(methylsulfonyl)-4-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide; N-(5-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)acetamide; N-(5-(6,7-dihydro-4H-furo[3,2-c]pyran-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(5-methyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(cyclopropylmethoxy)-4-((4-(1-methyl-1H-pyrazol-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-((1-hydroxycyclopropyl)methoxy)-4-((4-(1-methyl-1H-pyrazol-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(benzo[d]oxazol-2-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide; N-(4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide; N-(4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyrazolo[1,5-c]pyrimidin-2-yl)pyridin-2-yl)acetamide; N-(4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyrazolo[1,5-c]pyrimidin-2-yl)pyridin-2-yl)acetamide; N-(4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyrazolo[1,5-a]pyrimidin-2-yl)pyridin-2-yl)acetamide; N-(4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyrazolo[1,5-a]pyrimidin-2-yl)pyridin-2-yl)acetamide; N-(4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyrazolo[1,5-a]pyrimidin-5-yl)pyridin-2-yl)acetamide; N-(4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyrazolo[1,5-a]pyrimidin-5-yl)pyridin-2-yl)acetamide; or N-(5-(2,2-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-4-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide.
 20. A pharmaceutical composition comprising one or more compounds according to claim 3 or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
 21. A method of treating a disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 3, wherein the disease is an inflammatory or autoimmune disease. 